key: cord-285806-363ivs67
authors: Magro, Giuseppe
title: SARS-CoV-2 and COVID-19: is interleukin-6 (IL-6) the 'culprit lesion' of ARDS onset? What is there besides Tocilizumab? SGP130Fc
date: 2020-05-14
journal: Cytokine X
DOI: 10.1016/j.cytox.2020.100029
sha: 
doc_id: 285806
cord_uid: 363ivs67

Since the outbreak of COVID-19 many studies have been published showing possible therapies, here the author discusses the end of stage disease related drugs, like Tocilizumab which is currently being used in ARDS patients. In some patients, disease progression leads to an enormous secretion of cytokines, known as cytokine storm, among those cytokines IL-6 plays an important role. Here the author shows how IL-6 has both pro and anti-inflammatory properties, depending on the pathway of transduction: soluble (trans-signaling) or membrane-related (classic signaling), and suggests how targeting only the pro-inflammatory pathway, with SGP130Fc, could be a better option then targeting them both. Other possible IL-6 pathway inhibitors such as Ruxolitinib and Baricinitib are then analyzed, underlying how they lack the benefit of targeting only the pro-inflammatory pathway.

Coronaviruses are enveloped, positive-sense, single stranded RNA viruses that are distributed broadly among humans which cause respiratory, enteric, hepatic, and neurologic diseases 1 . SARS-CoV-2 is the agent responsible for the COVID-19, it is a beta coronavirus of group 2B with over 70% similarity in genetic sequence to SARS-CoV-1 2 . Acute respiratory distress syndrome (ARDS) is not an uncommon complication when disease can't be controlled 3 , the percentage of patients requiring ARDS treatment is about 10% for those who are actively infected. Total white blood count, lymphocytes, and platelets are lower than the average with extended activated thromboplastin time, increased C-reactive protein and muscle enzyme level.

Lymphocytes decrease with diseases progression. Secretion of cytokine, such as IL1B, IL1RA, IL6, IL7, IL8, known as cytokine storm, is associated with disease severity 3, 4 .

Therapeutic choices once disease has progressed will be discussed here.

SARS-CoV-1, MERS-CoV and SARS-CoV-2 show a relatively higher mortality rates then other coronaviruses, all of which are associated with the presence of a cytokine storm, this might suggest that inflammatory responses play a role in the pathogenesis. If that is the case, targeting the coronavirus alone with antiviral therapy might not be sufficient to reverse highly pathogenic infections 5 . These observations led to explore the usage of therapies that included interferons type I and II. Interferon beta displayed the best efficacy in reducing MERS-CoV replication in tissue culture 6, 7 . A randomized control trial is ongoing in South Arabia (MIRACLE Trial) to determine whether the combination of antivirals used in HIV infection such as Lopinavir/Ritonavir and Interferon beta could improve clinical outcomes in MERS-CoV infections 8 . In a humanized transgenic mouse MERS-CoV infection model, Remdesivir (a drug already being used against SARS-CoV-2 in patients with severe and moderate disease, GS-US-540-5773/4 Studies) showed more activity and efficacy in prophylactic and therapeutic use then the combination of Lopinavir/Ritonavir and Interferon beta 9 , this points towards the necessity to explore other options regarding immune system modulation and how control of viraemia is also essential.

The use of immunosuppressants like corticosteroids is quite controversial, for some it may be reasonable to counteract the effect of cytokine storm induced by the SARS-CoV-2. Although the recent open label study from Wu and colleagues showed a benefit for corticosteroids, for now clinical evidence does not support corticosteroid treatment for SARS-CoV-1 lung injury, as it could result in delayed viral clearence 10, 11 .

IL-6 can be produced by almost all stromal cells and by immune system cells, such as B lymphocytes, T lymphocytes, macrophages, dendritic cells, monocytes, mast cells and many non-lymphocytes, such as fibroblast and endothelial cells 12 . Main activators of the Interleuking-6 (IL-6) expression are IL-1beta and tumor necrosis factor (TNF-alfa), but many other factors can contribute to its secretion such as Toll-like receptors (TLRs), prostaglandins, adipokines, stress response and other cytokines 13 . In the early stage of the infectious inflammation, IL-6 is produced by monocytes and macrophages stimulated by the TLRs 14 .

IL-6 plays a crucial role in infectious diseases such as influenza where it has been shown how in a IL6 -/mice influenza specific CD4 + T cell response is impaired 15 . Loss of IL-6 results also in persistence of the influenza virus in the lung leading to extreme lung damage and death 16 . This shows how IL-6 limits influenza-induced inflammation and protects against lung damage 17 by promoting neutrophil survival in the lung 16 . IL-6 crucial role is not limited to influenza but also in other infections such as Herpes Simplex Virus-1 (HSV-1) infection where IL-6 deficient mice shows an increase in infection susceptibility 18 . In other scenarios, such as Respiratory Syncytial Virus (RSV) infections in mice, early depletion of IL-6, but not late, resulted in significant increase of the disease with an associated influx of cytotoxic CD8 + T cells 19 .

High levels of interleukin 6 (IL-6) and Interleukin 8 (IL 8) were found in the acute stage associated with lung lesions in SARS-CoV-1 patients. Especially IL-6 can induce the hyper-innate inflammatory response due to the SARS-CoV-1 invasion of the respiratory tract 20 . Interestingly, in human epithelial cells, SARS-CoV-1 was able to induce greater IL-6 when compared to influenza A virus 21 . Although in some murine viral infections IL-6 plays a protective and essential role in the resolution process, in others like in SARS-CoV-1 high levels of IL-6 were associated with severe inflammation and correlated with mortality in the mice 22, 23 . This happens also with SARS-CoV-2 in COVID-19 patients: some retrospective and meta-analysis studies show how elevated IL-6 and C-reactive protein (CRP) correlate with mortality and severe disease in comparison to moderate disease [24] [25] [26] [27] . More evidence suggests that critically ill patients with severe respiratory failure and SARS-CoV-2 have either immune dysregulation or macrophage-activation syndrome, both of which are characterized by pro-inflammatory cytokines. The immune dysregulation, in particular, is driven by the Interleukin-6 (IL- 6) and not by Interleukin-1beta (IL-1beta) 27 . Two key features of this immune dysregulation are: over-production of pro-inflammatory cytokines by monocytes and lymphocyte dysregulation with CD4 lymphopenia 27 .

A relevant study shows how IL-6 plays a major role in acute lung injury (ALI), proof of that was obtained in a murine model, where loss of IL-6 showed to alleviate the severity of ALI in response to acid respiration.

Moreover, it was shown how SARS-CoV-1 has the ability of inducing production of compounds like oxidized phospholipid (OxPL) both in humans and animals. OxPLs in turn induce cytokine production and acute lung injury via Toll Like Receptor 4 (TLR4) 28 . This is evidence of SARS-CoV-1 ability to indirectly induce acute lung injury and cytokine production, like that of IL-6 28, 29 . TLR4 is a transmembrane protein that belongs to the pattern recognition receptor family (PRR family), it recognizes molecules like lipopolysaccharide (LPS) thanks to an accessory protein known as MD-2 30 . TLRs activate transcription factors like NFkB, AP-1 and IRF inducing proinflammatory cytokines expressions and Interferon 1 [31] [32] [33] . TLR4 is associated not only with infections but also with tissue damage, and this damage-dependent pathway may be amplified in the acute stages of the infection. Of note, TLR4-null mice are highly resistant to infection by the mouse adapted influenza A virus 34 .

Protection against influenza infections in mouse models was shown to be achieved by targeting TLR4 with antagonists or with specific anti-receptor antibodies 35 . Another option in targeting host inflammatory response could then be targeting the cellular toll-like-receptor 4 (TLR4). Furthermore, TLR4 seems to regulate IL-6 secretion through the NFkB pathway 36 . This again points towards excessive activation of the innate immune response. Another proof of that is the damage shown to the pulmonary interstitial arteriolar walls that is more associated with the inflammatory response rather than the pathogenic effect of coronaviruses 37 .

An interesting fact is that SARS-CoV-1 can directly promote IL-6 secretion, this of course is not the only way it happens since IL-6 can be induced by so many types of cells and cytokines as mentioned above. Among all SARS-CoV-1 structural proteins (nucleocapsid N, spike S, envelop E and membrane M) only the nucleocapsid protein (N) significantly induced the activation of IL-6 promoter in human airway epithelial cell cultures 38 .

IL-6 gene expression is activated by the N protein which binds to the NF-kB regulatory element on IL-6 promoter and facilitates its translocation from cytosol to nucleus. The N protein is essential for IL-6 secretion to happen, since deletion of the C-terminus of the N protein resulted in the loss of function in the activation of IL-6 38 .

More evidence is emerging of many similarities between Macrophage Activation Syndrome (MAS) disease and COVID-19 pneumonia. Similarities include pathological findings and a "second wave" of cytokine secretion. The loss of "front line" anti-viral defence mechanism may be responsible for this "second wave" activation, thus prolonging IL-6 secretion 39 . Sustained IL-6 secretion has also been correlated to serum viral RNA load 40 -End of the initial phase of high viral load of COVID-19 (patient with no fever for more than 72 hours and/or more than 7 days from the symptoms onset) -Worsening of the respiratory condition requiring invasive or non invasive ventilation support -Elevated levels of IL-6 (more than 40 pg/ml); or high levels of D-Dimer and/or PCR and/or ferritin and/or progressive increasingly level of fibrinogen.

The signal transduction of IL-6 is induced by binding of IL-6 to its alpha receptor, Interleukin-6 Receptor (IL-6R). The complex formed by IL-6 and its receptor in turn activates a homodimer of the signal transduction beta-receptor gp130 with high affinity 44 . The gp130 receptor thereupon dimerizes and initiates intracellular signal transduction by activating the JAK/STAT and ras/MAP kinase pathways 45 . Gp130 is expressed on all cells of the human body. IL-6 Receptor instead is mainly found on hepatocytes, some leukocytes, and epithelial cells 46 . The IL-6 Receptor (IL-6R) protein is subjected to limited proteolysis by a metalloprotease activity which gives rises to a soluble form of IL-6R (sIL-6R) 47 . The majority of the soluble IL-6R found in the circulation is proteolytically cleaved from cells by the protease ADAM17 48, 49 . A minor portion of the sIL-6R is generated from an alternatively spliced mRNA 50 , but limited proteolysis remains the major mechanism by which the sIL-6R is generated 51 .

For signal transduction the IL-6R can either be membrane bound (classic pathway) or soluble (trans-signaling pathway) 51 . Those two different pathways of signal transduction seem to have different and divergent functions.

In the trans signaling, the complex of sIL-6R and IL-6 binds to and activates gp130 even on cells that do not express IL-6R 52 . This is an important mechanism since only a few cells in the human body express IL-6R, whereas the majority of cells do not show IL-6R expression 53, 54 . Since all cells express gp130, all of them are in theory possible target cells of IL-6 trans signaling 52 .

Trans-signaling is believed to be involved in chronic inflammation and cancer development 55 . Some animal models showed that when IL-6 was acting via the membrane bound IL-6R (classic signaling) it did so in a protective way, they also showed that inhibiting trans-signaling was superior to global blockade of IL-6 activity by neutralizing antibodies 56 , this was done using the IL-6 trans-signaling inhibitor sgp130Fc, which is a fusion protein of the gp130 with the Fc portion of a human immunoglobulin antibody 57, 58 . In a murine polymicrobial sepsis model, selective blockade of IL-6 trans-signaling with sgp130Fc improved survival up to 100%. Interestingly, treating these mice with anti-IL-6R antibodies did not prevent death of the mice 56 . This is a first hint of how targeting only the IL-6R with drugs like Tocilizumab might not be enough in a sepsis infectious model. Furthermore, it all points to the trans-signaling transduction being the harmful one (proinflammatory response), and the classic signaling transduction being the protective one (anti-inflammatory response) 59 . More evidence of that in some studies showing that elevated serum levels of IL-6, which are a marker of disease severity in the inflammatory acute lung injury during acute pancreatitis, were mediated by the trans-signaling transduction way, as sgp130Fc blocked the pancreatitis induced acute lung injury 60 .

Moreover in a mouse model of atherosclerosis sgp130Fc showed to reduce disease and showed significant regression of the atherosclerotic plaques, thus underlying the pro-inflammatory role of the trans-signaling pathway once more 61 . The sgp130Fc protein was shown not to interfere with IL-6 signaling via the membranebound IL-6R (mIL6-R). In contrast, IL-6 trans-signaling is completely blocked both in vitro and in vivo by the sgp130Fc protein 46 . Higher levels of the soluble IL-6 receptor(sIL-6R) are usually found in chronic inflammatory diseases and cancer 55 , in multiple myeloma for example high sIL-6R levels were correlated with poor survival 62 , sIL6R levels are also higher in chronic lymphocytic leukemia and lymphomas 63 . Locally increased sIL-6R concentrations were also found in the bronchoalveolar lavage fluid (BAL) of asthmatics 64 , and in malignant ascites from ovarian cancer patients, where it was associated with poor prognosis 65 .

Since sgp130 is expressed in all cells of the human body, under normal circumstances it is in molar excess over sIL-6R, therefore the concentration of the sIL-6R limits the capacity of the sIL-6R/sgp130 complex in the blood. During infections and inflammatory states, the concentration of sgp130 does not change, but the concentration of the sIL-6R increases up to 5 fold 66 . As a consequence, IL-6 and sIL-6R trans-signaling pathway stimulate all cells , which normally are not IL-6 target cells, like endothelial cells and smooth muscles cells 67 .

Recent studies about polymorphism within the IL-6R genes, showed how some IL-6 Receptor variants could be a much better substrate for the shedding protease ADAM17, resulting in a reduced response to inflammation and infectious states, in terms of sIL-6R increase 68 . Those individuals are also protected from many chronic inflammatory diseases 69 . This is another evidence of the pro-inflammatory role of the trans-signaling pathway and it could also be the explanation as to why some patients show a higher inflammatory response mediated by IL-6, similarly to what is happening with SARS-CoV-2 infection.

The essential role of IL-6 in fighting and clearing influenza infection has already been discussed above 19 . This protective role could be mediated by IL-6 classic signaling. This also happens for other infections like Listeria and mycobacteria infections, where IL-6 classic signaling via the membrane bound IL-6R is responsible for the defense of the body against these pathogens. Furthermore this defense is not affected by the selective blockade of IL-6 trans-signaling 70, 71 . In the animal model of listeriosis global blockade of IL-6 led to a dramatic increase in bacterial titers in spleen and liver. In contrast, selective blockade of IL-6 trans-signaling with the sgp130Fc protein did not result in increased bacterial titers, and thus was concluded that the classic signaling was involved in the protection of the body from bacterial infection 71 .

This shows the possibility to use the sgp130Fc protein as a potential inhibitor of the IL-6 pathway in COVID-19 patients, since it could preserve the regenerative and anti-inflammatory properties of the IL-6 classic pathway, and block the pro-inflammatory actions mediated by trans-signaling pathway 46 . It has been shown that the blockade of IL-6 trans-signaling using sgp130Fc was as efficient as the global blockade of IL-6 classic and trans-signaling using specific monoclonal antibodies 72 . SGP130Fc is mainly used in chronic inflammatory diseases (such as intestinal inflammation, rheumatoid arthritis, lupus erythematosus, neuroinflammation and cancer 51 ), but it has shown its efficacy also in acute inflammation 57 rate. This demonstrate that trans-signaling, rather than classic signaling, contributes to malaria lethality in mice 74 . IL-6 trans-signaling is also involved in the infiltration of granulocytes and macrophages during the late phase of an acute inflammation, and this happens when the trans-signaling triggers the secretion of chemokine MCP-1 in endothelial cells 57 

(mIL6-R) and are then unresponsive to IL-6 classic-signaling 75 . The infiltration of granulocytes and macrophages has been described as the possible cause of tissue damage in the acute lung injury, which is a severe complication of severe acute pancreatitis 60 .

From these data can be concluded that IL-6 classic signaling via the membrane bound IL-6R is antiinflammatory and protective, mainly via stimulation of intestinal regeneration, inhibition of epithelial cell apoptosis and defense against infections 46 .

In contrast, trans-signaling via the sIL6-R is believed to act in a rather pro-inflammatory way via recruitment of mononuclear cells, inhibition of T-cell apoptosis, and inhibition of regulatory T-cells differentiation 46 .

Interestingly, clinical pathological analysis of COVID-19 biopsy samples confirmed interstitial mononuclear inflammatory infiltrates in lung tissues, the same type of cells promoted by IL-6 trans-signaling 76 , therefore suggesting a possible involvement of trans-signaling pathway of IL-6 in COVID-19 patients with ARDS.

Moreover, IL-6 production sustained by circulating monocytes in COVID-19 is a different pathway from the one found in influenza infection, proof of that is Tocilizumab partially rescuing the immune dysregulation drive by SARS-CoV-2 27 .

To the author's knowledge sgp130Fc has not been tested in COVID-19 patients yet, thus the author suggests its possible use against SARS-CoV-2 in severe cases of COVID-19 patients, adopting the same criteria of Tocilizumab as to when to start the treatment. This option would provide the benefit of targeting only the pro-inflammatory trans-signaling pathway of IL-6, instead of targeting them both, which is something that happens with Tocilizumab 51 .

Both the trans-signaling and the classic-signaling pathways of IL-6 converge in the activation of the JAK/STAT pathway and the MAPK cascade 77 . The next step after binding of IL-6 to IL-6R and sgp130 is then to initiate intracellular signal transduction. The signal transfer is performed by the Janus-kinase/Signal transducer and activator of transcription (Jak/STAT)-,mainly STAT1, STAT3 isoforms [78] [79] [80] , mitogen-activated protein kinase (MAPK)-and phosphatidyl-inositol-3-kinase (PI3K)-pathway 44, 77 . Another possible way of counteracting IL-6 action is then to inhibit its intracellular transduction pathway, though in doing so the benefit of specifically targeting the pro-inflammatory trans-signaling pathway is lost. This can be done by inhibiting the JAK 1/2 pathway with drugs like Ruxolitinib. Ruxolitinib is a small drug belonging to the class of Janus kinase (JAK) inhibitors and currently clinically used in the treatment of JAK2 mutated myeloproliferative neoplasms, including myelofibrosis and polycythemia vera 81, 82 . It shows activity against the JAK2 isoform and also the JAK1 isoform, which plays a major role in the signaling pathway of inflammatory cytokines 83 . JAK3 seems to be less sensitive to ruxolitinib 84 , it also shows anti-inflammatory activity which may be beneficial in its clinical use 85 ; it is also implicated in the suppression of the harmful consequences of macrophage activation hemophagocytic lymphohistiocytosis 86 , which is an underrecognized hyperinflammatory syndrome characterized by fulminant and fatal hypercytokinemia with multi organ failure 87 . It has been proven that the expression of major inflammatory cytokines such as TNF alfa and IL6 was highly reduced in inflammatory human macrophages exposed to ruxolitinib 85 . It has also been shown through an analysis of mRNA expression of cytokines by PCR array that the major inflammatory cytokines , IL-6 and TNF alfa, were highly reduced and down-regulated by ruxolitinib at both protein and mRNA level 88 .

All these results point towards a possible use of Ruxolitinib as an IL-6 inhibitor like Tocilizumab in the advanced stages of COVID-19. This drug is currently being tested in some patients in Italy (CINC424, RUXOLITINIB).

Baricitinib has been suggested to be of therapeutic use against SARS-CoV-2 by Artificial Intelligence algorithms 89 . It is a selective and powerful JAK-STAT signaling inhibitor thus being effective against the consequences of the elevated levels of cytokines, not only being able of lowering IL-6 levels 90 , but it also has the potential to inhibit clathrin-mediated endocytosis and thereby inhibit viral infection of cells. It targets members of the numb-associated kinase (NAK) family ( AAK1 and GAK), the inhibition of which has been shown to reduce viral infection in vitro 91 . It can be administered orally and has acceptable side effect profile, besides having little interaction with CYP enzymes and drug transporters 89 . This makes Baricinitib a valid option in every phase of the viral infection, the early stages to reduce viral entry in the cells, and later stages for its anti-inflammatory properties.

Other monoclonal antibodies against IL-6 are sirukumab (CNTO136), olokizumab (CP6038), PF-423691, elsilimomab (BE-8), clazakizumab (BMS945429), which are in different phases of clinical trials to establish their efficacy and safety in varied disease states [92] [93] [94] [95] [96] [97] . Sarilumab, another monoclonal antibody against IL-6, is being tested in a clinical trial against COVID-19 (Sarilimumab COVID-19). Another drug that showed potential inhibition of IL-6 related JAK/STAT pathway is glatiramer acetate which showed potential to downregulate both IL-17 and IL-6 in the central nervous system in an autoimmune encephalitis 98 .

Here the author showed the viable options against the cytokine storm induced by SARS-CoV-2, showing that besides Tocilizumab, other options must be taken into account, and that inhibiting IL-6 is not a simple thing to do, since it has at least two different and divergent pathways; thus suggesting to inhibit only the proinflammatory response, the trans-signaling transduction with SGP130Fc, which seems a more reasonable choice then inhibiting both pathways. Here also other possible choices in counteracting IL-6 mediated activities are shown, like Ruxolitinib and Baricitnib, in the hope to find new possible strategies and discovering new properties of the drugs already available, since this would mean accelerating clinical trials as their side effects and tolerability in humans are already known. Figure1 . This diagram shows the classic signaling pathway (mediated by the membrane-bound form of IL-6 receptor, mIL6R) which is believed to be the antiinflammatory one and the trans-signaling pathway (mediated by the soluble form of IL-6 receptor, sIL6-R) which is believed to be the pro-inflammatory one. Tocilizumab inhibits both of them, SGP130Fc inhibits only the trans-signaling pathway.

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☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work

☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:  Evidence of a role for IL-6 in the pathology of SARS-CoV-2 and COVID-19

 IL-6 pathways: the classic (anti-inflammatory) and the trans-signaling

Possible use of SGP130Fc to selectively block the IL-6 trans-signaling pathway and thus only the pro-inflammatory pathway in SARS-CoV-2 infection

 Inhibition of the JAK/STAT pathway activated by IL-6: Ruxolitinib and Baricitinib