key: cord-0002554-dc9q6kqu
authors: Basil, Maria C.; Levy, Bruce D.
title: Specialized pro-resolving mediators: endogenous regulators of infection and inflammation
date: 2015-12-21
journal: Nat Rev Immunol
DOI: 10.1038/nri.2015.4
sha: f698533a935efdc028fa356ccd3beb72750f0c8c
doc_id: 2554
cord_uid: dc9q6kqu

Specialized pro-resolving mediators (SPMs) are enzymatically derived from essential fatty acids and have important roles in orchestrating the resolution of tissue inflammation — that is, catabasis. Host responses to tissue infection elicit acute inflammation in an attempt to control invading pathogens. SPMs are lipid mediators that are part of a larger family of pro-resolving molecules, which includes proteins and gases, that together restrain inflammation and resolve the infection. These immunoresolvents are distinct from immunosuppressive molecules as they not only dampen inflammation but also promote host defence. Here, we focus primarily on SPMs and their roles in lung infection and inflammation to illustrate the potent actions these mediators play in restoring tissue homeostasis after an infection. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nri.2015.4) contains supplementary material, which is available to authorized users.

Acute inflammation is a vital response to infection that is initiated within seconds of pathogen detection 1 . Granulocytes are rapidly recruited to sites of infection 2 , where they become activated and augment the resident capacity of infected tissue to kill and ultimately clear the pathogen 3 . These early events in the host response to infection are essential for survival and are coordinated by several families of pro-inflammatory mediators, including lipid mediators (such as prostaglandins and leukotrienes), cytokines and chemokines. These pro-inflammatory mediators have overlapping and distinct functions and ultimately induce an increase in vascular permeability and orchestrate leukocyte recruitment. This leads to the cardinal signs of tissue inflammation -namely calor, rubor, tumor, dolor and potentially functio laesa (FIG. 1) .

Recently, a new array of molecules that function in the resolution of inflammation were elucidated and named specialized pro-resolving mediators (SPMs) 4, 5 . Many of these SPMs are produced during the acute inflammatory response 6 , and their structure, biosynthesis and organic synthesis have been recently reviewed (see REF. 5) . Typically, acute inflammatory responses to pathogens are self-limiting, and there is a growing appreciation that SPMs have pivotal anti-inflammatory and anti-infective roles in tissue catabasis 4 . For effective resolution of inflammation to occur in tissues, cessation of granulocyte recruitment is required in conjunction with the recruitment and differentiation of macrophages, which help clear inflammatory cells and tissue debris to restore tissue homeostasis 7 . Granulocytes in the tissue undergo apoptosis during the resolution of inflammation to prevent bystander tissue injury occurring from the release of potentially toxic cellular contents 8 . Removal of apoptotic neutrophils prompts a switch from a pro-to an anti-inflammatory macrophage pheno type, which is a prerequisite for macrophage efferocytosis and egress via the lymphatic vessels 9 . Efferocytosis also leads to further production of additional SPMs that signal for restoration of vascular integrity, regeneration and/or repair of injured tissues, remission of fever by inhibition of proinflammatory lipid mediators and cytokines, and relief of inflammatory pain 10 . Together, the SPMs and these cellular events in resolution can be summarized as the newly recognized five cardinal signs of resolution (FIG. 1) .

In this Review, we address the functions of SPMs in infectious immunity and chronic inflammatory diseases, with a focus on how SPMs affect lung physiology and pathology in these diseases. Recent discoveries [11] [12] [13] [14] [15] regarding anti-inflammatory, anti-infective and proresolving roles for SPMs point to their potential translational applications in harnessing endogenous resolution responses for novel host-directed therapeutic strategies in sterile and infectious inflammation. Additional roles in these homeostatic processes for non-lipid mediators of resolution will not be covered in detail here but have been recently reviewed (see . Cellular and molecular mechanisms for catabasis have now been determined in multiple organ systems and diseases. Here, we will primarily focus on lung infection and inflammation. The resolution responses that occur in non-pulmonary sites of infection and inflammation have recently been reviewed (see REFS 7, [19] [20] [21] . Finally, we consider how new therapeutic strategies that incorporate immunoresolvents may have the potential to synergize with antibiotics and to mitigate the growing problem of antibiotic resistance.

In response to pathogen invasion or tissue injury, polyunsaturated fatty acids are released locally from membrane phospholipids or delivered to sites of inflammation by tissue oedema for subsequent conversion to specialized mediators by cells in the exudates 22 . Within minutes, the generation of eicosanoids (that is, prostaglandins and cysteinyl leukotrienes) from arachidonic acid (C20:4n-6) metabolism helps to direct peripheral blood neutrophils to infected sites. Prostaglandin E 2 (PGE 2 ) and PGI 2 regulate blood flow, whereas leukotriene C 4 (LTC 4 ) and LTD 4 regulate vascular permeability 1, 23 . Furthermore, neutrophils transmigrate towards chemotactic gradients of LTB 4 (REF. 24 ). With selected cytokines, chemokines and complement components (namely C5a and C3b), these eicosanoids induce neutrophil entry into the tissue to engulf and kill invading pathogens 3, 25 . Early in the acute inflammatory response, the origins are laid for biosynthesis of resolution-phase mediators through lipid mediator class-switching, in which arachidonic acid metabolism switches from the production of leukotrienes to the production of lipoxins -the lead family of pro-resolving mediators 26 . Disruption of lipoxin formation or lipoxin receptor availability delays the resolution response [27] [28] [29] [30] .

As a class, the SPMs are enzymatically derived from essential fatty acids, including arachidonic acid, eicosapentaenoic acid (EPA; C20:5n-3) and docosa hexaenoic acid (DHA; C22:6n-3) in a lipoxygenase (LOX)dependent manner (FIG. 2) . SPMs are stereo selective, and complete stereochemical assignment for the majority of the SPMs has been established (reviewed in REF. 31 ). Lipoxins are formed by transcellular biosynth esis via multiple distinct pathways. One pathway involves leukocyte-derived 5-LOX and platelet-derived 12-LOX in the vasculature 32 . A second pathway involves the conversion of arachidonic acid by epithelial cell-, eosinophilor monocyte-derived 15-LOX and leukocyte-derived 5-LOX 33, 34 . Although aspirin inhibits prostaglandin production, aspirin-mediated acetylation of cyclooxygenase 2 (COX2; also known as PTGS2) leads to the conversion of arachidonic acid to 15(R)-hydroxyeicosatetraenoic acid (15(R)-HETE), which can serve as a substrate for 5-LOX-mediated conversion to 15-epi-lipoxins (also known as aspirin-triggered (AT) lipoxins) 35 . Of note, in the absence of aspirin, 15(R)-HETE can also be produced by cytochrome P450 enzymes to act as a substrate for 15-epi-lipoxin transcellular biosynthesis 36, 37 .

In addition to lipoxins, resolving exudates also contain pro-resolving mediators derived from omega-3 fatty acids. These include resolvins, protectins and maresins (reviewed in REF. 38) (FIG. 2) . E-series and D-series resolvins are enzymatically derived from EPA and DHA, respectively. Similarly to 15-epi-lipoxins, resolvins are generated through interactions between aspirin-acetylated COX2 and LOX activities 39 . For example, in the vasculature, resolvin E1 (RvE1) transcellular synthesis in the presence of aspirin is notable for transformation of EPA to 18(R)-hydroxyEPA (18(R)-HEPE) by aspirin-acetylated COX2 in endothelial cells and 18(R)-HEPE conversion to RvE1 by leukocyte 5-LOX 40, 41 . There are two major series of resolvins that are derived from DHA, namely D-series resolvins (RvD1-RvD6) and their positional AT isomers (AT-RvD1-RvD6) 42 . The D-series resolvins are enzymatically generated by 15-LOX-mediated conversion of DHA to 17(S)-hydroperoxyDHA (17(S)-HpDHA) Figure 1 | Cardinal signs of inflammation and its resolution. Tissue-and organism-level responses to inflammation have been well recognized for centuries and can be summarized as the 'five pillars of inflammation'; namely, calor (fever), rubor (redness), tumor (swelling and oedema), dolor (pain) and functio laesa (loss of function). With the recognition that the resolution of inflammation is an active process, recent research has identified molecular and cellular processes that promote catabasis. These can be summarized as the 'five pillars of resolution'; that is, removal of microorganisms, dead cells and debris, restoration of vascular integrity and perfusion, tissue regeneration, remission of fever and relief from inflammatory pain. and subsequent transformation by 5-LOX. For the AT-resolvins, DHA is initially converted by aspirinacetylated COX2 to 17(R)-HpDHA that can also serve as a substrate for 5-LOX-mediated transformation to epimeric resolvins. Additional families of pro-resolution mediators derived from DHA have also been identified in resolving inflammatory exudates that display protective bioactivities, namely protectins and maresins 43, 44 . At sites of inflammation, 15-LOX-derived 17(S)-HpDHA can be converted to protectin D1 (REF. 45) , and 12-LOX-derived 14(S)-HpDHA can be converted to maresin 1 (MaR1) (for a detailed review, see REF. 31 ). The respiratory tract mucosa in health is enriched with DHA 46 , and both 17(S)-hydroxy-DHA and protectin D1 are generated in human airways 47 .

These SPMs exert their bioactions as molecular signals via agonist properties at cognate receptors (FIG. 2) . The lipoxin A 4 (LXA 4 ) receptor ALX (also known as FPR2) is a G protein-coupled receptor that binds LXA 4 and 15-epi-LXA 4 with high affinity. High-affinity receptors have also been identified for RvE1 (namely, chemokine-like receptor 1 (CMKLR1; also known as CHEMR23)) 41 , for RvD1 (namely, the probable G protein-coupled receptor GPR32) and for RvD2 (namely, the N-arachidonyl glycine receptor GPR18) 48, 49 . Of interest, RvD1 can also activate ALX with high affinity and is Stereoselective mediators that enhance host defence, resolve tissue inflammation and stimulate tissue regeneration have been described 4 . These specialized pro-resolving mediators (SPMs) are produced in a spatio-temporally regulated manner from essential polyunsaturated fatty acids (PUFAs) that are either released enzymatically by phospholipase A 2 (PLA 2 ) from cell membranes for secondary conversion by biosynthetic enzymes or delivered with oedema fluid from plasma to exudates. The principal SPM families are lipoxins from arachidonic acid (C20:4n-6; in light blue), as well as the E-series resolvins from eicosapentaenoic acid (C20:5n-3; in pink) and D-series resolvins, protectins and maresins from docosahexaenoic acid (C22:6n-3; in green). The SPM precursors eicosapentaenoic acid and docosahexaenoic acid are essential omega-3 PUFAs. Representative members of these families, their structures and receptors are shown here. CMKLR1, chemokine-like receptor 1; GPR32, probable G protein-coupled receptor 32; LX, lipoxin; MaR1, maresin 1; NPD1, neuroprotectin D1; RvD1, resolvin D1; RvE, resolvin E. equipotent to LXA 4 in binding and activating this receptor 49 . In addition to RvD1, AT-RvD1 and RvD3 bind to GPR32 with high affinity [49] [50] [51] . These SPMs display potent receptor-mediated cell-specific actions (TABLE 1) . Pharmacological structure activity relationships support receptor-dependent signalling mechanisms for the remaining SPMs; however, the molecular identity of their cognate receptors is still to be determined.

As is the case with lipoxins, defects in these SPM pathways can undermine resolution and contribute to 27, 30, [52] [53] [54] [55] . Failure of the resolution response may occur as a result of defects in receptor expression, enzyme synthesis, intracellular signalling or nutritional deficiencies in essential polyunsaturated fatty acids. Functional roles bring these structurally distinct families of lipoxins, resolvins, protectins and maresins together as SPMs -a genus of endogenous molecules that pharmacologically act as immunoresolvents 4 .

Pro-resolving mediators are active in the picogram to nanogram dose range, whereby they are able to control inflammation, limit tissue damage, shorten resolution intervals, promote healing and alleviate pain in experimental models of inflammation and resolution. These fatty acid-derived mediators are part of a larger resolution programme that includes annexin A1 protein 16 , several cytokines (for example, transforming growth factor-β (TGFβ) and interleukin-10 (IL-10)) 11 , microRNAs 51 and carbon monoxide 56 . Inhibitors of cyclin-dependent kinases can also pharmacologically promote resolution 57 .

Counter-regulation of the acute inflammatory response evolved to neutralize and eliminate pathogens and enable repair of inflamed or injured tissues. The main cellular events of resolution are the cessation of neutrophil influx and activation, in conjunction with macrophage recruitment, efferocytosis and phagocytosis of microorganisms and debris 6, 58 . As a class of mediators, SPMs are partly defined by their overlapping function to limit neutrophil tissue accumulation, counter-regulate pro-inflammatory cytokines and encourage macrophage phagocytosis (FIG. 3) . During efferocytosis, phagocytes generate SPMs that serve as autacoids to inhibit neutrophil activation, increase apoptotic cell expression of CC-chemokine receptor 5 (CCR5) for chemokine clearance and promote bacterial killing and efferocytosis by macrophages (TABLE 1 ). In addition to phagocytes, lymphoid cells have vital roles in host defence, express SPM receptors and can serve as cellular effectors for SPMs. In this section, we highlight selected cell types with important functions in resolution and host defence that respond to SPMs.

For tissue resolution of inflammation, it is essential to prevent further neutrophil entry, inhibit tissue neutrophil activation and promote the clearance of apoptotic neutrophils. All of these cellular actions are mediated by SPMs. Of particular note, SPMs initiate leukocyte shape changes that limit neutrophil migration in vitro 22 Macrophages. Both tissue-resident and recruited inflammatory macrophages serve pivotal roles in responses to infection and inflammation. SPMs augment macrophage functions to clear microorganisms, tissue debris and apoptotic cells (reviewed in REF. 6 ). In contrast to neutrophils, SPMs lead to macrophage shape changes that prepare the cells for phagocytosis of microorganisms, apoptotic cells and debris 9, 12, 62, 63 . Key macrophage actions for SPMs include increased phagocytosis and IL-10 production and decreased pro-inflammatory cytokine production 9,64,65 .

promote the resolution of an inflammatory response by inducing neutrophil 66 and eosinophil apoptosis 67 , which is a non-inflammatory mechanism for cell removal from tissues and has a crucial role in successful resolution of the inflammatory response 8 . Apoptotic granulocytes can subsequently be removed by tissue macrophage efferocytosis before tissues are exposed to their potentially toxic contents. By accelerating granulocyte apoptosis, NK cells can limit pathogen-mediated inflammatory responses. During a self-limited inflammatory response, resolution of inflammation is an active process governed by specialized pro-resolving mediators (SPMs) that transmit both anti-inflammatory (red) and pro-resolving (blue) actions to leukocytes and tissue-resident cells. This class of endogenous immunoresolvents induces an anti-inflammatory response by inhibiting granulocyte migration and activation, disrupting sensory neuron activation and dampening cytokine production by a variety of structural cells, including epithelial cells, endothelial cells and fibroblasts. SPMs have a multipronged action to regulate sentinel innate lymphoid cells to decrease cytokine and increase amphiregulin production. These mediators also promote resolution by inducing regulatory T cells to control innate lymphoid cells, stimulating natural killer cells to trigger granulocyte apoptosis and engaging macrophages in a non-phlogistic manner to engulf bacteria and noxious stimuli, and clear apoptotic cells by efferocytosis. IL-5, interleukin-5; O 2 − , superoxide; TNF, tumour necrosis factor; TRPV1, transient receptor potential cation channel subfamily V member 1. Decrease neutrophil infiltration and pro-inflammatory cytokine levels 88

Restore impaired phagocyte activity of macrophages 90

RvE1 is bone-protective in murine models, mediating preservation and accelerating regeneration 69 . In response to epithelial-derived cytokines, such as IL-25, IL-33, thymic stromal lymphopoietin and mast cell-derived prostanoids (that is, PGD 2 ), ILC2s generate type 2 cytokines -IL-5 and IL-13 -in an antigenindependent manner 67 . Similarly to NK cells, ILC2s express receptors for pro-resolving mediators, including LXA 4 and RvE1 (REF. 67 ). LXA 4 and MaR1 can potently inhibit ILC2 release of pro-inflammatory cytokines 67, 70 . MaR1 also promotes amphiregulin release by ILC2s 70 , a protective response for restoring lung mucosal homeostasis after influenza infection 71 .

Lymphocytes. Adaptive immune cells also have important roles in the active resolution of inflammation. CCR5 expression on apoptotic, activated T cells acts to sequester pro-inflammatory cytokines and terminate inflammation; a mechanism that is augmented by SPMs 72 . RvE1 decreases the production of pro-inflammatory cytokines, such as IL-23 and IL-17, to dampen the adaptive immune response, particularly T helper 17 (T H 17) cell responses 73 . Regulatory T cells are pivotal to controlling effector T cell proliferation and activation. Of note, MaR1 was recently identified as a potent inducer for the formation of regulatory T cells in vivo and in vitro in combination with TGFβ 70 . Only limited information is available on SPM actions on B cells, but RvD1 was recently shown to augment B cell antibody production and increase the number of antibody-producing B cells in a mouse influenza vaccination model 74 . These emerging data on the regulation of adaptive immunity by SPMs extend their range of actions and suggest a pivotal role for these imuno resolvents in the transition from innate to adaptive inflammation.

In mucosal host defence, transmigrating neutrophils initiate a respiratory burst and degranulation response to invading pathogens; however, excessive neutrophil activation can cause 'bystander' tissue damage and contribute to pathobiology of mucosal inflammatory disease 75 . During resolution, the activated neutrophils are cleared apically from the intestinal lumin by decay accelerating factor (also known as CD55), which is an anti-adhesive molecule 76 . SPMs potently inhibit neutro phil trans-epithelial migration and the production of pro-inflammatory cytokines by epithelial cells 77 .

In addition, SPMs promote decay accelerating factor expression in mucosal epithelia as well as expression of the anti-infective peptide bactericidal permeability-increasing protein and the lipopolysaccharide (LPS) detoxification enzyme alkaline phosphatase 78, 79 .

Although the role of SPMs has only recently been uncovered in tissue homeostasis, there is already a push to understand the functions of SPMs in infections. Studies on the role of SPMs in the modulation of host responses to various infectious diseases have highlighted a new therapeutic opportunity for targeting the host in infectious inflammation to complement antibiotic therapy.

Some recent examples are provided in TABLE 2 and the following sections, in which we consider the roles of SPMs in bacterial, viral and fungal diseases. 

Pneumonia. Although pneumonia typically initiates a self-limiting acute inflammatory response, in some individuals the inflammation is so severe that it leads to life-threatening hypoxaemia and respiratory failurenamely, the acute respiratory distress syndrome (ARDS) -which is discussed in greater detail in the next section. In Escherichia coli-induced pneumonia, the SPM LXA 4 promotes neutrophil apoptosis by inducing the phosphorylation of BCL-2-associated death promoter (BAD) and reducing the expression of the anti-apoptotic protein myeloid cell leukaemia sequence 1 (MCL1) 80 , whereas RvE1 promotes neutrophil apoptosis through activation of caspases 81 . In both cases, promotion of neutrophil death leads to a reduction in the severity of acute lung inflammation 81, 82 . These findings highlight a direct interaction between the SPMs and apoptotic pathways in immune cells. In addition, RvE1 enhances bacterial clearance and reduces local production of proinflammatory cytokines in E. coli aspiration pneumonia, which results in enhanced survival of mice 13 .

Bacterial periodontitis is a well-established experimental model that has been used to elucidate the role of SPMs in controlling localized bacterial infection, its associated tissue damage and systemic effects. Periodontitis is generally caused by a polymicrobial insult, resulting in the generation of biofilms, overgrowth of resident Gram-negative bacteria in the oral cavity and mucosal inflammation. The disease process is thought to be mediated by an overly robust immune response to the bacteria, including to Porphyromonas gingivalis in chronic infection and Actinobacillus spp. in the localized aggressive form of the disease. Periodontitis also carries a more generalized implication to human health, as localized periodontitis elicits a systemic response, increasing systemic inflammation and risk for accelerated atherosclerosis 82, 83 . In localized P. gingivalis infection models, introduction of stable analogues of lipoxins and AT-lipoxins results in a reduction of neutrophil recruitment to the site of infection 84 . In a rabbit model of the same infection, rabbits that either transgenically overexpress 15-LOX, the enzyme responsible for production of lipoxins and protectins, or are treated with a topical formulation of LXA 4 had a reduction in leukocyte infiltration in inflammation at the site of injury and a reduction in bone loss 85 , highlighting a suppressive role for the lipoxins in the control of localized inflammation in this chronic infection. Furthermore, the systemic response to infection is attenuated, resulting in a decrease in neutrophil-platelet interactions 86 and limiting generalized systemic inflammation, as indicated by a reduction in biomarkers such as C-reactive protein 61 .

Resolvins also have a role in promoting protection against bacterial periodontitis. In localized aggressive periodontitis (LAP), RvE1 suppresses neutrophil superoxide generation 87 , neutrophil infiltration 88 and the production of pro-inflammatory cytokines 88 , and enhances macrophage activity 89 . At least some of its actions are mediated through its interaction with CMKLR1, which is highly expressed on macrophages and dendritic cells (DCs) 41 . In models of LAP, treatment of animals with topical RvE1 results in a decrease in localized and systemic inflammation and allows the host to regenerate lost tissue and bone mass 61 . The ability of RvE1 to reestablish homeostasis at the local tissue level proceeds in part through its ability to restore phagocyte activity of macrophages, which is impaired in LAP 90 . Lipoxin analogues or AT-lipoxins have no significant effect on neutrophil activity in LAP, which is in contrast to chronic periodontitis, in which LXA 4 has a regulatory role, highlighting a context-specific mechanism for the pro-resolving mediators.

In a similar manner to periodontitis, a pattern of localized and systemic control of inflammation is seen in mouse models of Lyme disease. In 5-LOX-deficient mice, which have a defect in SPM production, the development of arthritis in animals infected with Borrelia burgdorferi is similar to that in wild-type animals; however, the absence of lipoxins and resolvins impairs the host ability to resolve arthritis, resulting in chronic disease 91 and a lack of control of the chronic systemic inflammatory response long after the triggering infectious agent has been cleared.

Tuberculosis. The protective roles for SPMs in acute infections, such as pneumonia, are also integral to the host immune response to Mycobacterium tuberculosis. In this host response, there is a delicate balance between pro-inflammatory mediators, such as PGE 2 and LTB 4 , and pro-resolving mediators, such as LXA 4 , that can dictate the intensity of the pathogen-mediated inflammation as well as microbial clearance. In a mouse model of M. tuberculosis infection, there is a rise in the levels of both the pro-inflammatory LTB 4 and the pro-resolving LXA 4 after infection, with LXA 4 high levels persisting throughout the chronic infection 92 . In animals deficient in 5-LOX (a deficiency that leads to defective leuko triene and lipoxin production), M. tuberculosis infection is associated with enhanced survival 92 . Host lipoxin generation is related to M. tuberculosis strain virulence, suggesting a vital role for SPMs in modulating the host inflammatory responses to M. tuberculosis. Excessive production of either LTB 4 or LXA 4 can result in aberrant host responses to M. tuberculosis infection that, intri guingly, converge on dysregulated expression of TNF 15 . This accentuates the importance of both pro-inflammatory and pro-resolving responses for host defence and regulation of pathogen-mediated inflammation. Crucial roles for arachidonic acid metabolism in immune responses may be linked to the different infectious rates observed with human variants in the ALOX5 (encoding 5-LOX) locus 93 and the LTA4H (which encodes LTA 4 hydrolase, an enzyme involved in the final step of LTB 4 production) locus 94 , which both appear to disrupt LTB 4 and LXA 4 production as well as altering protection against naturally occurring M. tuberculosis infection. Together, these findings suggest that a combinatorial approach to tuberculosis therapy would be most effective, including antibiotics to help endogenous mechanisms kill the microorganism and SPMs to control the host immune response.

Sepsis is the most serious complication of acute bacterial infection. The host response in sepsis leads to diffuse systemic immune dysregulation that progresses rapidly, frequently resulting in shock. In Gram-negative bacteria-initiated sepsis, there appears to be a protective and potentially therapeutic role for lipid mediators. In mice with sepsis after caecal ligation and puncture, treatment with LXA 4 reduced the production of proinflammatory cytokines, while simultaneously promoting a reduction in Gram-negative bacteria loads that improved survival 95, 96 . Resolvins also have an important protective role in sepsis models. RvD2 serves as a potent regulator of the systemic inflammatory response in sepsis 14 . This reduction in pro-inflammatory signals is a consequence, in part, of reduction in nuclear factor-κB (NF-κB) activity 13, 60, 96 . Treatment of septic mice with RvD2 leads to a profound reduction in the production of cytokines, including IL-6, IL-10 and interferon-α (IFNα), and leukocyte infiltration to the site of infection is reduced. Of interest, control of the inflammatory response leads to an overall reduction in bacterial loads, both at the local site of insult and systemically within the blood, and an improvement in overall animal survival 14 . Sepsis is a disease of overwhelming infectious insult, compounded by an overly robust inflammatory response, whereby treatment with anti-inflammatory therapies potentially subjects the host to further harm. Modulation of pro-resolution responses appears to promote dampening of the inflammatory response while still allowing for adequate, and possibly improved, clearance of the bacterial infection. The ability to clear the source of infection while still limiting the immune response provides an attractive therapeutic paradigm for this disease of substantial health-care burden.

The biological demand for an initial robust response against a bacterial insult is juxtaposed against the need to control prolonged and overly exuberant inflammatory responses that are potentially harmful, raising potential challenges for the therapeutic use of pro-resolving mediators. For example, in a pneumosepsis model, early treatment with LXA 4 appears to limit the immune response by decreasing leukocyte infiltration, reducing bacterial clearance and worsening the survival rate 97 . By contrast, in the same model, later treatment with LXA 4 had positive effects, allowing for adequate clearance of infection but dampening the protracted and pathological immune response, therefore enhancing survival 97 . In the future, timing and dosing considerations and concomitant antibiotic use will be important for developing SPM therapeutic strategies in sepsis.

Overall, in bacterial infection, SPMs have significant therapeutic potential with ongoing research focused on their anti-infective mechanisms and optimal dose and timing strategies to harness their beneficial actions. In animal models, the augmentation of resolution also appears to reduce the needed dosage for antibiotics in the clearance of bacterial infections 12, 95 . Given the worldwide crisis of emerging antibiotic resistance, therapies that could reduce antibiotic usage provide an attractive alternative in the quest to develop new and enhanced antimicrobial therapeutic approaches.

Influenza. Viral pathogens also appear to interact with the host in a way that is modifiable by pro-resolving factors. Influenza viruses are a well-suited model to understand the role of resolution mediators and the mechanisms in viral infections, as different strains of the virus elicit varied host immune responses and outcomes. In studies that compare more virulent strains of the influenza virus to less virulent strains, pro-resolving mediators inversely correlated with biological activity of the virus. More virulent strains of influenza led to suppression of lipoxins 98 , which is associated with enhanced viral dissemination. Protectin D1 has pivotal and multiple roles in regulating viral pathogenicity. More virulent influenza strains, such as H5N1, downregulate protectin D1 levels, and the pathogenicity of various isolates correlates inversely with levels of protectins 99 . In addition to host inflammatory responses, protectin D1 has direct antiviral actions on influenza; both protectin D1 and its isomer protectin DX (which is formed by LOXmediated double oxygenation) interfere with viral RNA nuclear export machinery, thereby limiting viral replication [100] [101] [102] . Treatment of infected mice with protectin D1 improves survival (FIG. 4) even when administered as late as 48 hours after infection 102 , at a time when current antiviral therapies are no longer significantly effective 103 . 104 . Promotion of these two alternative macrophage fates appears related to RSV-induced COX2 (REF. 105) and LXA 4 -and RvE1-mediated protective actions 106 . Host responses to RSV again highlight roles for SPMs and lipid mediator class-switching in the initial control and eventual clearance of infection.

Herpes simplex virus (HSV) ocular infection represents another example in which local control of the virus results from a robust inflammatory response, with long-term consequences of chronic inflammation that persists after clearance of the virus, including the potential for eventual blindness from stromal keratitis. In animals with HSV, topi cal administration of RvE1 results in decreased influx of effector CD4 + T cells (both T H 1 cells and T H 17 cells) and neutro phils, reduced production of pro-inflammatory cytokines, including IFNγ and IL-6, increased levels of the anti-inflammatory cytokine IL-10 and decreased pro-angiogenic factors 107 . Overall, RvE1 significantly decreased stromal keratitis. Similar results have been demonstrated for protectin D1 (REF. 108 ), further illustrating the potential therapeutic benefits of SPM control of pathogen-mediated inflammation to lessen injury to bystander tissues.

The interaction of the host immune system with infectious insults from viruses represents a novel opportunity for exploitation of SPMs. Finding the delicate balance between the need for a sufficient immune response to clear infection and rapid dampening of that Nature Reviews | Immunology response to prevent host damage is a well-suited target for SPMs, and further research is needed to identify opportunities for optimizing this balance in human viral infectious disease.

Responses to parasitic infections also appear to engage SPMs in host defence. With Toxoplasma gondii, there is a robust DC response with production of IL-12 (REF. 109 ). Lipoxins are generated in vivo during toxoplasmosis and act in an autacoid mechanism on DCs via ALX leading to reduction of CCR5 expression and diminished IL-12 production 110 . In animal models, 5-LOX deficiency results in the production of significantly more IL-2 and IFNγ compared with wild-type animals, as well as severe encephalitis and increased mortality, all of which can be reversed by administration of LXA 4 analogues 111 . Similar protective roles for lipoxins have been suggested for other intracellular and extracellular parasites, including Angiostrongylus costaricensis 112 , Plasmodium spp. 113 and Trypanosoma cruzi 114 .

The generation of SPMs may not always be beneficial to the host. As discussed previously in M. tuberculosis infections, experimental models that strongly favour the generation of lipoxins over leukotrienes can have detrimental effects on pathogen clearance. If given early in pharmacologically large amounts, SPM regulation of the pathogen-mediated immune response may impair microbial clearance. In addition, there are now examples identified of select pathogens using local SPM production as an immune evasion and survival strategy. T. gondii is able to generate components of SPM biosynthetic pathways, resulting in local collaboration with host cells to increase lipoxin production with the consequence of a dampened immune response to T. gondii 115 . Recruitment of neutrophils, lymphocytes and eosinophils to the site of infection are all decreased by this mechanism 115 . In addition to T. gondii, the opportunistic bacteria Pseudomonas aeruginosa can express a secreted LOX that can augment SPM production in the local milieu to modulate host defence 116 . Similarly, Candida albicans can biosynthesize RvE1 that limits IL-8-mediated neutrophil infiltration in the host, enabling colonization 117 . These examples further illustrate the delicate balance between the pathogen and the host in SPM production and control of host immune responses.

Non-infectious inflammation is a common and often devastating cause of human disease. Most current therapies rely on blunting the inappropriate immune response through the use of anti-inflammatory medications, all of which have significant undesirable side effects, including increasing the host susceptibility to infection. Although the roles of SPMs have been investigated in many inflammatory diseases (TABLE 3) , below we focus on the role of SPMs in inflammation of the lung by highlighting data from preclinical animal models.

protectin D1 production is increased. Protectin D1 limits influenza pathogenicity by directly interacting with the RNA replication machinery to inhibit viral RNA nuclear export. In particularly virulent strains of influenza, such as the H5N1 avian (A) strain, protectin D1 formation is not sufficiently upregulated, leading to more efficient viral replication and host demise. Treatment of the host with exogenous protectin D1 can restore inhibition of viral RNA export, thereby limiting viral replication and improving host survival.

Asthma is a disease of excessive airway inflammation and hyperresponsiveness induced by irritant triggers and subsequently driven by a multitude of factors, including the trafficking of neutrophils, eosinophils and the generation of type 2 inflammatory responses in many cases. Severe asthma is poorly responsive to existing therapies, and it is charac terized by increased oxidative stress and decreased lipoxin production in the airways 55, 118, 119 . Recently, the increased oxidative stress in uncontrolled asthma was linked to decreased lipoxin levels through a compensatory increase in soluble epoxide hydrolase activity 118 . As a consequence of the soluble epoxide hydrolase activity, levels of 14,15-epoxyeicosatrienoic acid levels were decreased, which adversely impacted lipoxin production 118 , providing a biochemical mechanism for oxidative insults to disrupt lung resolution programmes. Low SPM levels in severe asthma are likely to have the functional consequence of chronic inflammation and airway hyper reactivity because airway LXA 4 blunts leukotriene-mediated bronchoprovocation in humans 120 , and in mice stable analogues of LXA 4 block airway hyperresponsiveness, mucus metaplasia and type 2 lung inflammation 121, 122 , and accelerate resolution of the inflammatory response 73 .

RvE1 has protective effects in preclinical models of allergic lung inflammation; it decreases eosinophil recruitment, type 2 cytokine production and airway hyperresponsiveness 73, 123 . RvE1 targets NK cells in mouse models of asthma through the RvE1 receptor CMKLR1, promoting NK cell migration and cytotoxicity. With NK cell depletion, the pro-resolving function of RvE1 is partially impaired 68 . In allergic inflammation, RvE1 increases lipoxin formation, suggesting the possibility of redundant pathway effects to limit chronic inflammation. RvE1 inhibits IL-6, IL-23 and IL-17 release, thereby dampening the development and activation of T H 17 cells. Similarly to RvE1, lipoxins can inhibit IL-17 production but do not inhibit IL-23, which is indicative of convergent but not overlapping signalling pathways. Of note, as mentioned above, RvE1 and LXA 4 also engage distinct receptors, namely CMKLR1 and ALX, respectively 73 . RvD1 acts in a complementary manner, similarly promoting the resolution of eosinophil tissue accumulation and pro-inflammatory responses with a macrophage directed action to enhance allergen phagocytosis and clearance 63 . Similarly, protectin D1 has been shown to promote resolution of the lung inflammatory response and block airway hyperresponsiveness 47 . Of interest, protectin D1 regulates IL-5 and IL-13 but not IL-4 levels, suggesting that ILC2s rather than T H 2 cells are likely to be a principal cellular target for protectin D1. It is notable that protectin D1 levels are decreased in exhaled breath condensates during asthma exacerbations 47 .

Recently, lung sensory neurons were identified as early inducers of ILC2 activation in type 2 lung inflammation 124 . These activated neurons express transient receptor potential (TRP) channels, which can serve as SPM targets. Of note, mouse models have suggested a role for RvD1, RvE1, neuroprotectin D1 (NPD1) and MaR1 in attenuating pain by inhibition of TRP channels [125] [126] [127] [128] . Because SPMs act at these pain receptors in the nervous system and on inflammatory pathways, these findings suggest that regulation of sensory neuron activation could be a crucial mechanism for SPM inhibition of both pain and lung inflammation. Together, these findings highlight an integrated network of pro-resolving mediators in asthma and allergic inflammation and suggest several potential therapeutic targets.

Chronic obstructive pulmonary disease. Chronic obstructive pulmonary disease (COPD) is a pulmonary inflammatory disease most often triggered by cigarette smoke and propagated through maladaptive and prolonged pro-inflammatory responses, predisposing the host to recurrent infections. Pro-inflammatory lipid mediators, including leukotrienes, have been observed at elevated levels in patients with COPD 119 . Roles for SPMs remain to be determined in these individuals. In addition to LXA 4 , the acute phase reactant serum amyloid A (SAA) can also interact with ALX, and it is increased in COPD exacerbations 27 , which are largely caused by viral and bacterial respiratory tract infections. In acute exacerbations of COPD, levels of SAA are more than 2 log orders higher than LXA 4 (REF. 27 ).

In sharp contrast to LXA 4 , when SAA engages ALX, it triggers a pro-inflammatory, neutrophil driven response. Although SAA-mediated inflammation is glucocorticoidresistant, it can be regulated by pharmacological dosing of lipoxins 27 , suggesting a new therapeutic approach for steroid-resistant lung inflammation.

The role of resolvins in COPD is a subject of active investigation. Cigarette smoke exposure results in the development of classically activated macrophages, which produce a pro-inflammatory response. Alternatively activated, or M2, macrophages also play a part in the clearance of inhaled particles and quelling of the initial response to the cigarette smoke. RvD1 polarizes cigarette smoke-exposed macrophages towards the M2 pathway, resulting in enhanced phagocytosis as well as upregulated production of IL-10 (REF. 64 ). RvE1 also acts on cigarette smoke-activated macrophages, reducing superoxide production and limiting inflammation 129 . The ability of resolvins to polarize the macrophage population towards the M2 phenotype suggests a novel mechanism for SPM control in this chronic inflammatory disorder.

Cystic fibrosis is a genetic disorder with multi-organ defects caused by a single mutation. Patients with cystic fibrosis have viscous respiratory tract secretions, recurrent airway infections and an over-exuberant immune response, eventually resulting in the deterioration of lung function. Genetic modifier analysis suggests that patients with cystic fibrosis who carry a polymorphism in PTGS2 (encoding COX2) that leads to reduced production of pro-inflammatory mediators have improved clinical status 130 . Profiling of lipid mediators in the airways of patients with cystic fibrosis showed that lipoxin levels may be lower in these patients compared with healthy control subjects 54 . Moreover, patients with cystic fibrosis who had detectable levels of RvE1 in the airways showed improved lung function compared with patients without any detectable RvE1 131 ). Furthermore, in animal models of cystic fibrosis, lipoxin administration suppresses neutrophil infiltration and reduces bacterial burden, resulting in an overall reduction in disease severity 54 .

Fibrotic lung disease. Multiple pulmonary injurious exposures have a unifying endpoint in the development of extensive tissue scarring, resulting in poor gas exchange, air movement and demise of the host. These fibrotic lung diseases can be mediated by a poorly controlled inflammatory response that triggers a fibrotic response in a maladaptive attempt to heal the damaged lung parenchyma. These diseases represent a devastating human burden, as very few treatments exist to slow or reverse this fibrotic process. Pro-resolving mediators could represent a novel strategy in a sparse arsenal. Bleomycin is an important chemotherapeutic agent but carries a known risk of pulmonary fibrosis. Treatment with LXA 4 or 15-epi-LXA 4 results in an attenuation of pulmonary fibrosis in animals exposed to bleomycin through reduction of the pro-fibrotic cytokine TGFβ 132 , as well as an increase in the preva lence of M2 macrophages 133 , both resulting in decrease fibrotic matrix and improved pulmonary function. In humans, scleroderma lung disease is characterized by idiopathic progressive lung inflammation and fibrosis and, of interest, patients with scleroderma lung disease underproduce pro-resolving mediators, in comparison to their pro-inflammatory counterparts 134 .

Acute respiratory distress syndrome. ARDS is a prevalent condition with high rates of morbidity and mortality. It is characterized by an overly robust inflammatory response to infection (for example, pneumonia and sepsis) or injury that fills the alveoli with oedema and pus, resulting in life-threatening respiratory failure. Many unsuccessful attempts have been made to therapeutically target an inflammatory pathway to limit this over-exuberant host response. In contrast to these anti-inflammatory strategies, a pro-resolving therapeutic strategy directed at harnessing host pro-resolving mechanisms is showing promise in preclinical model systems. Using a sterile model of ARDS from gastric acid aspiration, an important clinical risk factor for ARDS, several SPMs, including LXA 4 , 15-epi-LXA 4 , RvE1, RvD1 and MaR1, have proven effective as pharmacological agents in limiting acute lung inflammation and injury, and accelerating lung tissue catabasis 13, 29, 59, 60, 135 . Because SPMs engage endogenous resolution pathways, these mediators have the potential to both decrease pathogen-mediated inflammation and enhance host defence, which distinguishes SPMs from immunosuppressive agents. Early inflammation in ARDS is mediated by platelet-neutrophil interactions 59, 136 , and this interaction can lead to transcellular production of lipoxins or of the most recently discovered member of the SPM family, MaR1 (REF. 59 ). Treatment with MaR1 is organ protective and limits the extent of lung inflammation. Furthermore, the timing of MaR1 production appears specific and regulated, as does the production of RvD1 (REF. 137 ). Together, these findings highlight the potential roles SPMs could have in decreasing the severity and duration of ARDS and, more generally, the data support a targeted pro-resolving approach as a new therapeutic strategy for this devastating condition that is currently without available medical treatment.

As momentum grows to leverage these natural resolution pathways for rational new therapeutic strategies for diseases of acute and chronic inflammation, it is essential to clarify the roles of SPMs in human host defence and in the regulation of pathogen-mediated inflammation. As discussed above, preclinical data for bacterial infection points to important and pivotal roles for lipid mediators, in particular SPMs, in the regulation of host responses to infection 12, 13 with the potential for host SPM-directed interventions to decrease antibiotic requirements 12, 95 . In addition, for viral host responses, SPMs lessened the severity of influenza and HSV infections 102, 107, 108 . Several lines of evidence have suggested dysregulation of SPM pathways in several human diseases 27, 47, 55 .

Clinical trials with SPM analogues that resist metabolic inactivation are still in early phases. A recent study of children with infantile eczema compared a topical stable LXA 4 analogue (15-(R/S)-methyl-LXA 4 ) to the current clinical approach of topical corticosteroids (specifically, mometasone). 15-(R/S)-methyl-LXA 4 was well tolerated and controlled clinical symptoms and disease as effectively as topical steroids 138 . This trial is the first to report successful treatment with an SPM in humans. Moreover, for allergic diseases, inhaled LXA 4 decreases LTC 4 -initiated bronchoprovocation in patients with asthma 120 . Several clinical trials using a topical formulation of an RvE1 analogue for ocular conditions are also underway (NCT01639846, NCT01675570, NCT00799552 and NCT02329743).

Host responses to infection naturally trigger both an acute inflammatory response and its resolution.

Counter-regulation of pathogen-mediated inflammation is an active process with specific cellular and biochemical events that are tightly regulated in health. With the identification of several families of endogenous pro-resolving mediators, their potent anti-inflammatory properties are now being determined. Distinct from immunosuppressive agents, these endogenous proresolving mediators generally display protective actions in host defence, including direct antimicrobial actions. There is still much to be done to more fully understand the intersection of these novel endogenous pathways in control of pathogen-mediated inflammation and the diversity of their mechanisms in microbial pathogenesis. The abundant presence of SPMs in human healthy breast milk 139 suggests important protective actions for these mediators. Clinically, acute infections are principally treated with antibiotics with current approaches devoid of host-directed therapy. In light of the current serious threat of emerging pathogens, in particular those that display antibiotic resistance, the development of therapies to augment host anti-infective mechanisms are needed. Members of the growing new genus of SPMs or their bioactive stable analogues represent potential candidates to harness endogenous antiinflammatory resolution mechanisms to limit overly exuberant pathogen-mediated inflammation in future therapeutic strategies.

Points of control in inflammation

Involvement of plateletendothelial cell adhesion molecule-1 in neutrophil recruitment in vivo

Acute lower respiratory tract infection

Pro-resolving lipid mediators are leads for resolution physiology

Protectins and maresins: new pro-resolving families of mediators in acute inflammation and resolution bioactive metabolome

Resolution of inflammation: the beginning programs the end

Proresolving lipid mediators and mechanisms in the resolution of acute inflammation

Phagocytic docking without shocking

Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators

Apoptotic cells, through transforming growth factor-β, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages

Molecular circuits of resolution: formation and actions of resolvins and protectins

This report illustrates that SPMs can enhance the antimicrobial actions of ciprofloxacin and vancomycin to promote bacterial clearance

The anti-inflammatory and proresolving mediator resolvin E1 protects mice from bacterial pneumonia and acute lung injury

This study shows that SPM actions increase clearance of E. coli and decrease host inflammation to enhance survival

Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis

This study highlights the role of resolvins in a complex bacterial infection with suppression of both local bacterial and systemic inflammatory responses

This report highlights the balance between pro-inflammatory and pro-resolving mediators in the clearance of M

Annexin A1 and glucocorticoids as effectors of the resolution of inflammation

A blast from the past: clearance of apoptotic cells regulates immune responses

Gaseous mediators in resolution of inflammation

New insights into the resolution of inflammation

Lipoxins and aspirin-triggered lipoxins in resolution of inflammation

Atherosclerosis -a matter of unresolved inflammation

Rapid appearance of resolvin precursors in inflammatory exudates: novel mechanisms in resolution

Lipoxin A4 antagonizes cellular and in vivo actions of leukotriene D4 in rat glomerular mesangial cells: evidence for competition at a common receptor

Tonic inhibition of chemotaxis in human plasma

Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases

Lipid mediator class switching during acute inflammation: signals in resolution

Serum amyloid A opposes lipoxin A4 to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease

Anti-inflammatory role of the murine formyl-peptide receptor 2: ligand-specific effects on leukocyte responses and experimental inflammation

Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury

Resolvin E1 and protectin D1 activate inflammationresolution programmes

This study provides crucial evidence that resolution is an active process and inhibiting SPM formation leads to a 'toxic' resolution

Resolvins and protectins in inflammation resolution

Lipoxin formation during human neutrophil-platelet interactions. Evidence for the transformation of leukotriene A4 by platelet 12-lipoxygenase in vitro

Human alveolar macrophages have 15-lipoxygenase and generate 15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid and lipoxins

Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes

Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions

Aspirin-triggered lipoxins (15-epi-LX) are generated by the human lung adenocarcinoma cell line (A549)-neutrophil interactions and are potent inhibitors of cell proliferation

Aspirin-triggered 15-epi-lipoxin A4 (ATL) generation by human leukocytes and murine peritonitis exudates: development of a specific 15-epi-LXA4 ELISA

The resolution of inflammation: the devil in the flask and in the details

Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals

Novel functional sets of lipidderived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal anti-inflammatory drugs and transcellular processing

Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1

Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their endogenous aspirin-triggered epimers

Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells

Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions

Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy-containing docosatrienes

Association of cystic fibrosis with abnormalities in fatty acid metabolism

Protectin D1 is generated in asthma and dampens airway inflammation and hyperresponsiveness

Identification of resolvin D2 receptor mediating resolution of infections and organ protection

Resolvin D1 binds human phagocytes with evidence for proresolving receptors

Resolvin D1 receptor stereoselectivity and regulation of inflammation and proresolving microRNAs

MicroRNAs in resolution of acute inflammation: identification of novel resolvin D1-miRNA circuits

Resolution of inflammation in murine autoimmune arthritis is disrupted by cyclooxygenase-2 inhibition and restored by prostaglandin E2-mediated lipoxin A4 production

Inducible cyclooxygenase may have anti-inflammatory properties

Defective lipoxin-mediated antiinflammatory activity in the cystic fibrosis airway

Diminished lipoxin biosynthesis in severe asthma

Cell-cell interactions and bronchoconstrictor eicosanoid reduction with inhaled carbon monoxide and resolvin D1

Cyclin-dependent kinases 7 and 9 specifically regulate neutrophil transcription and their inhibition drives apoptosis to promote resolution of inflammation

Lipoxins: resolutionary road

Maresin 1 biosynthesis during platelet-neutrophil interactions is organ-protective

Aspirin-triggered resolvin D1 reduces mucosal inflammation and promotes resolution in a murine model of acute lung injury

Resolvin E1 regulates inflammation at the cellular and tissue level and restores tissue homeostasis in vivo

Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages

Resolvin D1 and aspirin-triggered resolvin D1 promote resolution of allergic airways responses

A novel anti-inflammatory and proresolving role for resolvin D1 in acute cigarette smokeinduced lung inflammation

17(R)-Resolvin D1 differentially regulates TLR4-mediated responses of primary human macrophages to purified LPS and live E. coli

Human NK Cells induce neutrophil apoptosis via an NKp46-and Fas-dependent mechanism

This study identifies new cellular mechanisms for SPMs to regulate innate lymphoid cell responses, such as NK cell-mediated granulocyte apoptosis and regulation of ILC2 cytokine release

NK cells are effectors for resolvin E1 in the timely resolution of allergic airway inflammation

Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages

Cutting edge: maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation

Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus

Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression

Resolvin E1 regulates interleukin 23, interferon-γ and lipoxin A4 to promote the resolution of allergic airway inflammation

The specialized proresolving mediator 17-HDHA enhances the antibody-mediated immune response against influenza virus: a new class of adjuvant?

Lipoxin A4 modulates transmigration of human neutrophils across intestinal epithelial monolayers

Antiadhesive role of apical decay-accelerating factor (CD55) in human neutrophil transmigration across mucosal epithelia

Lipoxin A 4 regulates bronchial epithelial cell responses to acid injury

Resolvin E1-induced intestinal alkaline phosphatase promotes resolution of inflammation through LPS detoxification

Lipid mediator-induced expression of bactericidal permeability-increasing protein (BPI) in human mucosal epithelia

15-epi-lipoxin A4 inhibits myeloperoxidase signaling and enhances resolution of acute lung injury

Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation

Periodontal disease is associated with brachial artery endothelial dysfunction and systemic inflammation

Role for periodontitis in the progression of lipid deposition in an animal model

Lipoxin A 4 analogues inhibit leukocyte recruitment to Porphyromonas gingivalis: a role for cyclooxygenase-2 and lipoxins in periodontal disease

Reduced inflammation and tissue damage in transgenic rabbits overexpressing 15-lipoxygenase and endogenous anti-inflammatory lipid mediators

Lipoxin A 4 inhibits Porphyromonas gingivalis-induced aggregation and reactive oxygen species production by modulating neutrophil-platelet interaction and CD11b expression

RvE1 protects from local inflammation and osteoclast-mediated bone destruction in periodontitis

Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation

Resolvin E1 metabolome in local inactivation during inflammation-resolution

Impaired phagocytosis in localized aggressive periodontitis: rescue by Resolvin E1

5-Lipoxygenase-deficient mice infected with Borrelia burgdorferi develop persistent arthritis

Host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase-dependent lipoxin production

ALOX5 variants associated with susceptibility to human pulmonary tuberculosis

The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans

Combination therapy of 15-epi-lipoxin A4 with antibiotics protects mice from Escherichia coli-induced sepsis*

Lipoxin a4 increases survival by decreasing systemic inflammation and bacterial load in sepsis

Dual role of lipoxin A4 in pneumosepsis pathogenesis

Lethal dissemination of H5N1 influenza virus is associated with dysregulation of inflammation and lipoxin signaling in a mouse model of infection

Lipidomic profiling of influenza infection identifies mediators that induce and resolve inflammation

Influenza-time to target the host? New Engl

Role of omega-3 PUFA-derived mediators, the protectins, in influenza virus infection

The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza

Effects of oseltamivir treatment on duration of clinical illness and viral shedding and household transmission of influenza virus

Control of RSV-induced lung injury by alternatively activated macrophages is IL-4Rα-, TLR4-, and IFN-β-dependent

Respiratory syncytial virus (RSV) infection induces cyclooxygenase 2: a potential target for RSV therapy

Role of the lipoxygenase pathway in RSV-induced alternatively activated macrophages leading to resolution of lung pathology

Controlling herpes simplex virusinduced ocular inflammatory lesions with the lipidderived mediator resolvin E1

Neuroprotectin D1 reduces the severity of herpes simplex virus-induced corneal immunopathology

In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin 12 by dendritic cells and their redistribution to T cell areas

Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity

Parasite-induced lipoxin A4 is an endogenous regulator of IL-12 production and immunopathology in Toxoplasma gondii infection

Cyclooxygenase-2-derived prostaglandin E2 and lipoxin A4 accelerate resolution of allergic edema in Angiostrongylus costaricensisinfected rats: relationship with concurrent eosinophilia

Lipoxin A 4 and 15-epi-lipoxin A 4 protect against experimental cerebral malaria by inhibiting IL-12/IFN-γ in the brain

Protective role of acetylsalicylic acid in experimental Trypanosoma cruzi infection: evidence of a 15-epi-lipoxin A 4 -mediated effect

Exogenous pathogen and plant 15-lipoxygenase initiate endogenous lipoxin A4 biosynthesis

The opportunistic pathogen Pseudomonas aeruginosa carries a secretable arachidonate 15-lipoxygenase

Candida albicans modulates host defense by biosynthesizing the proresolving mediator resolvin E1

Lipoxin generation is related to soluble epoxide hydrolase activity in severe asthma

Severe asthma is associated with a loss of LX4, an endogenous anti-inflammatory compound

The effects of lipoxin A4 on airway responses in asthmatic subjects

Multi-pronged inhibition of airway hyper-responsiveness and inflammation by lipoxin A 4

Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism

Resolvin E1 dampens airway inflammation and hyperresponsiveness in a murine model of asthma

silencing nociceptor neurons reduces allergic airway inflammation

Resolving TRPV1-and TNF-αmediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1

Resolvin D2 is a potent endogenous inhibitor for transient receptor potential subtype V1/ A1, inflammatory pain, and spinal cord synaptic plasticity in mice: distinct roles of resolvin D1, D2, and E1

Macrophage proresolving mediator maresin 1 stimulates tissue regeneration and controls pain

Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions

Resolvin E1 maintains macrophage function under cigarette smoke-induced oxidative stress

Prostaglandin-endoperoxide synthase genes COX1 and COX2 -novel modifiers of disease severity in cystic fibrosis patients

Metabolomic profiling of regulatory lipid mediators in sputum from adult cystic fibrosis patients. Free Radic

ATLa, an aspirin-triggered lipoxin A4 synthetic analog, prevents the inflammatory and fibrotic effects of bleomycin-induced pulmonary fibrosis

Pulmonary antifibrotic mechanisms aspirin-triggered lipoxin A 4 synthetic analog

Cyclooxygenase-and lipoxygenase-derived eicosanoids in bronchoalveolar lavage fluid from patients with scleroderma lung disease: an imbalance between proinflammatory and anti-inflammatory lipid mediators

Lovastatin decreases acute mucosal inflammation via 15-epi-lipoxin A4

Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation

Endogenous expression pattern of resolvin D1 in a rat model of self-resolution of lipopolysaccharide-induced acute respiratory distress syndrome and inflammation

Efficacy and safety of 15(R/S)-methyl-lipoxin A 4 in topical treatment of infantile eczema

This study reports the first randomized control trial of a SPM in the treatment of human disease; the use of lipoxin in eczema was associated with excellent clinical outcomes

High levels of anti-inflammatory and pro-resolving lipid mediators lipoxins and resolvins and declining docosahexaenoic acid levels in human milk during the first month of lactation

Design of lipoxin A4 stable analogs that block transmigration and adhesion of human neutrophils

Lipoxin A4 and B4 inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells

Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity: a 'stop' signaling switch for aspirin-triggered lipoxin A4

Lipoxin A 4 and lipoxin B 4 inhibit chemotactic responses of human neutrophils stimulated by leukotriene B 4 and N-formyl-L-methionyl-L-leucyl-L-phenylalanine

LXA4, aspirin-triggered 15-epi-LXA4, and their analogs selectively downregulate PMN azurophilic degranulation

Lipoxin A4 and B4 are potent stimuli for human monocyte migration and adhesion: selective inactivation by dehydrogenation and reduction

Lipoxin A4 and aspirin-triggered 15-epilipoxin A4 inhibit peroxynitrite formation, NF-κB and AP-1 activation, and IL-8 gene expression in human leukocytes

Lipoxins are potential endogenous anti-inflammatory mediators in asthma

Effects of lipoxin A4 on chemotaxis and degranulation of human eosinophils stimulated by platelet-activating factor and N-formyl-L-methionyl-L-leucyl-L-phenylalanine

Lipoxin A-induced inhibition of human natural killer cell cytotoxicity: studies on stereospecificity of inhibition and mode of action

Lipoxins stimulate prostacyclin generation by human endothelial cells

Aspirin-triggered lipoxin A4 blocks reactive oxygen species generation in endothelial cells: a novel antioxidative mechanism

Aspirin-triggered Lipoxin A4 inhibition of VEGF-induced endothelial cell migration involves actin polymerization and focal adhesion assembly

Lipoxin A4 inhibits IL-1β-induced IL-6, IL-8, and matrix metalloproteinase-3 production in human synovial fibroblasts and enhances synthesis of tissue inhibitors of metalloproteinases

Lipoxin A4 inhibits proliferation of human lung fibroblasts induced by connective tissue growth factor

Modulation of human airway smooth muscle migration by lipid mediators and Th-2 cytokines

Resolvin E1 promotes mucosal surface clearance of neutrophils: a new paradigm for inflammatory resolution

Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis

Identification and structure determination of novel anti-inflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenoic acid

Resolvin D1 and its aspirin-triggered 17R epimer. Stereochemical assignments, antiinflammatory properties, and enzymatic inactivation

Resolvin D series and protectin D1 mitigate acute kidney injury

The docosatriene protectin D1 is produced by TH2 skewing and promotes human T cell apoptosis via lipid raft clustering

Maresin-1 reduces the proinflammatory response of bronchial epithelial cells to organic dust

Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: implications for the neuropathogenesis of HIV disease

Lipid mediators in innate immunity against tuberculosis: opposing roles of PGE2 and LXA4 in the induction of macrophage death

Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair

Proresolving nanomedicines activate bone regeneration in periodontitis

Resolvin E1 and chemokine-like receptor 1 mediate bone preservation

Resolvin D2 restores neutrophil directionality and improves survival after burns

The endogenous pro-resolving mediators lipoxin A4 and resolvin E1 preserve organ function in allograft rejection

Lipoxin A4 attenuates acute rejection via shifting TH1/TH2 cytokine balance in rat liver transplantation

The resolvin D1 analogue controls maturation of dendritic cells and suppresses alloimmunity in corneal transplantation

A synthetic eicosanoid LX-mimetic unravels host-donor interactions in allogeneic BMT-induced GvHD to reveal an early protective role for host neutrophils

Aspirin-triggered lipoxin A4 stimulates alternative activation of microglia and reduces Alzheimer disease-like pathology in mice

A role for docosahexaenoic acidderived neuroprotectin D1 in neural cell survival and Alzheimer disease

25-dihydroxyvitamin D3 and resolvin D1 retune the balance between amyloid-β phagocytosis and inflammation in Alzheimer's disease patients

Neuronal phagocytosis by inflammatory macrophages in ALS spinal cord: inhibition of inflammation by resolvin D1

Aspirin-triggered lipoxin enhances macrophage phagocytosis of bacteria while inhibiting inflammatory cytokine production

Lipoxin a4 analogs attenuate induction of intestinal epithelial proinflammatory gene expression and reduce the severity of dextran sodium sulfate-induced colitis

Resolvin E1, an endogenous lipid mediator derived from eicosapentaenoic acid, prevents dextran sulfate sodium-induced colitis

Omega-3 fatty acid-derived mediators 17(R)-hydroxy docosahexaenoic acid, aspirin-triggered resolvin D1 and resolvin D2 prevent experimental colitis in mice

Resolvin D1 decreases adipose tissue macrophage accumulation and improves insulin sensitivity in obese-diabetic mice

Impaired local production of proresolving lipid mediators in obesity and 17-HDHA as a potential treatment for obesity-associated inflammation

Resolvin D1 reverses chronic pancreatitis-induced mechanical allodynia, phosphorylation of NMDA receptors, and cytokines expression in the thoracic spinal dorsal horn

A role for the mouse 12/15-lipoxygenase pathway in promoting epithelial wound healing and host defense

Resolvin E1 (RX-10001) reduces corneal epithelial barrier disruption and protects against goblet cell loss in a murine model of dry eye

Conjunctival goblet cell secretion stimulated by leukotrienes is reduced by resolvins D1 and E1 to promote resolution of inflammation

Resolvin D1 and aspirin-triggered resolvin D1 regulate histamine-stimulated conjunctival goblet cell secretion

Resolvin E1 improves tear production and decreases inflammation in a dry eye mouse model

Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis

Transfection of rat kidney with human 15-lipoxygenase suppresses inflammation and preserves function in experimental glomerulonephritis

Lipoxin A4 and benzo-lipoxin A4 attenuate experimental renal fibrosis

Resolvins E1 and D1 inhibit interstitial fibrosis in the obstructed kidney via inhibition of local fibroblast proliferation

BML-111, a lipoxin receptor agonist, modulates the immune response and reduces the severity of collagen-induced arthritis

The precursor of resolvin D series and aspirin-triggered resolvin D1 display anti-hyperalgesic properties in adjuvant-induced arthritis in rats

Resolvin E1 protects the rat heart against reperfusion injury

Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development

Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression

Omega-3 fatty acid-derived mediator, Resolvin E1, ameliorates 2,4-dinitrofluorobenzeneinduced atopic dermatitis in NC/Nga mice

Effects of D-series resolvins on behavioral and neurochemical changes in a fibromyalgia-like model in mice

Resolvin D1 attenuates activation of sensory transient receptor potential channels leading to multiple anti-nociception

The authors wish to acknowledge C. N. Serhan for his helpful advice in the preparation of this manuscript. This work was funded in part by US National Institutes of Health grants HL122531, U10HL109172, U01HL108712 and P01GM095467.

The authors declare competing interests: see Web version for details.

ClinicalTrials.gov: http://www.clinicaltrials.gov