key: cord-0779830-dka4vvmj authors: Li, Lun; Acioglu, Cigdem; Heary, Robert F.; Elkabes, Stella title: Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases date: 2020-10-08 journal: Brain Behav Immun DOI: 10.1016/j.bbi.2020.10.007 sha: bf9bbcc8c6575c7d839118ac5de9c54b53f805bb doc_id: 779830 cord_uid: dka4vvmj Central nervous system (CNS) innate immunity plays essential roles in infections, neurodegenerative diseases, and brain or spinal cord injuries. Astrocytes and microglia are the principal cells that mediate innate immunity in the CNS. Pattern recognition receptors (PRRs), expressed by astrocytes and microglia, sense pathogen-derived or endogenous ligands released by damaged cells and initiate the innate immune response. Toll-like receptors (TLRs) are a well-characterized family of PRRs. The contribution of microglial TLR signaling to CNS pathology has been extensively investigated. Even though astrocytes assume a wide variety of key functions, information about the role of astroglial TLRs in CNS disease and injuries is limited. Because astrocytes display heterogeneity and exhibit phenotypic plasticity depending on the effectors present in the local milieu, they can exert both detrimental and beneficial effects. TLRs are modulators of these paradoxical astroglial properties. The goal of the current review is to highlight the essential roles played by astroglial TLRs in CNS infections, injuries and diseases. We discuss the contribution of astroglial TLRs to host defense as well as the dissemination of viral and bacterial infections in the CNS. We examine the link between astroglial TLRs and the pathogenesis of neurodegenerative diseases and present evidence showing the pivotal influence of astroglial TLR signaling on sterile inflammation in CNS injury. Finally, we define the research questions and areas that warrant further investigations in the context of astrocytes, TLRs, and CNS dysfunction. Taken together, these findings indicate that activation of TLRs modulates both immune 291 and non-immune functions of astrocytes, and induces astrocyte reactivity. It is likely that the 292 net consequence of astroglial TLR stimulation is context-dependent and influenced by the 293 pathological environment in which the cells function. In the following sections, we will discuss 294 the outcomes of astroglial TLR activation in CNS infections, injuries, and diseases. Our goal is to 295 highlight the broad diversity of responses mounted by astrocytes in distinct pathologies and to 296 underline the commonalities and divergences. (Ketzler et al., 1990) . The early interactions between viruses that enter the CNS and the local cells determine The aforementioned studies provide insights into the influence of astroglial TLR 540 signaling in the response mounted to foreign pathogens. However, as stated before, TLRs are 541 also activated by endogenous ligands in disease and injury and are principal inducers of the 542 sterile inflammation frequently observed in neurodegenerative diseases and in CNS injuries. The following sections will discuss the beneficial and detrimental responses of astrocytes to CNS injury includes TBI and SCI, as well as ischemic and hypoxic damage that can result 681 from occlusion of arteries that supply blood to the CNS or from the damage of blood vessels 682 following TBI or SCI. An initial tissue injury is often followed by progressive cell death, 683 demyelination, and axonal degeneration, which exacerbates the damage. TLR2, TLR4, and TLR9 are the best studied TLRs in the context of CNS injury. However, 685 specific information regarding the contribution of astroglial TLR signaling to CNS injury is scarce. 686 In the healthy brain and spinal cord, the levels of astroglial TLR4 are very low and not readily astroglial inflammatory response via effects on TLR3 and its downstream effector NF-379 κB expression in a strain-dependent manner and promotes pro-inflammatory cytokine and 380 chemokine release. Genetic silencing of TLR3 expression or pharmacological inhibition of TLR3 381 signaling reduces this pro-inflammatory response Serramia 394 et al., 2015) which is paralleled by increased pro-inflammatory cytokine and chemokine 395 production However, it is not yet known whether the increased TLR2, TLR4, and TLR5 expression is directly 397 linked to elevated inflammatory mediator production by infected astrocytes. TLR7 and TLR9 398 transcript levels significantly increase in ZIKV infected human astrocyte cultures The highly contagious severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 2020. Although the primary target of SARS-CoV-2 is the respiratory system, an 406 increasing percentage of COVID-19 patients present neurological symptoms including anosmia, 407 ageusia, encephalitis, seizures, and stroke However, 422 there is no consensus about the principal mode of entry due to the lack of information 423 regarding this issue. In COVID-19 patients with severe disease, the levels of plasma GFAP and 424 neurofilament light chain protein (NFL), markers of astrocyte and axonal damage Observations on the predecessors to SARS-CoV-2, namely, SARS-CoV and Middle East 427 Respiratory Syndrome (MERS)-CoV, which caused the earlier SARS and MERS pandemics, also 428 indicate the presentation of neurological symptoms by affected individuals The presence of viral RNA in the brain 430 and CSF of individuals with SARS further supports the notion of neurotropism However, there is not enough evidence showing the presence of viral RNA in 432 the CSF of MERS patients. SARS-CoV viral particles have been detected in hypothalamic and 433 cortical neurons and this was paralleled by neurodegeneration Infection of human DPP4 transgenic 441 mice with MERS-CoV causes neuronal damage with infiltration of inflammatory cells SARS-CoV-2, or MERS are scarce, investigations on 448 other coronaviruses have been performed and could provide insights into potential 449 mechanisms Infected astrocytes robustly upregulate the expression of class I major 452 histocompatibility complex (MHC I), which could contribute to virus-induced pathology 453 When iPSC-derived astrocytes obtained from familial and 609 sporadic PD patients were co-cultured with ventral midbrain dopaminergic neurons, they neuronal survival could not be ruled out TLRs contribute to PD, and other α-synucleinopathies, by mediating the associated 616 neuroinflammation and glial activation and exposure of primary rat astrocyte 621 cultures to neuron-derived α-syn, in vitro, significantly increases TLR2 transcript levels and 622 induces an inflammatory gene expression profile in astrocytes In addition to TLR2, TLR4 signaling has been implicated in α-syn-induced astrocyte 635 activation and inflammatory responses. α-syn-induced release of TNF-α, CXCL1, and IL-6 is 636 significantly reduced in TLR4 -/-astrocytes compared to TLR4 +/+ astrocytes. However, TLR4 637 deficiency does not affect α-syn uptake by astrocytes Thus, α-syn induces the astroglial inflammatory 642 reaction by acting through both TLR2 and TLR4 signaling (Figure 2). However, the 643 internalization of α-syn is likely mediated by TLR2 ALS is an adult onset neurodegenerative disorder that selectively causes the loss of 650 upper and lower motor neurons in the brain and spinal cord The majority of ALS cases are sporadic, but approximately 10% of the cases are 652 familial These 657 mice develop symptoms when they reach late adulthood and the disease progresses over time 658 leading to death Analysis of post-mortem tissue obtained from sporadic ALS patients showed a global 662 increase in TLR2 and TLR4 transcript and protein levels in the spinal cord Moreover, TLR4 modulates the viability of 706 astrocytes following SCI. Pro-inflammatory M1 microglia/macrophages release cytotoxic 707 molecules in response to injury which upregulate the expression of TLR4 and the necroptotic 708 markers, receptor-interacting protein 3 (RIP3) and mixed lineage kinase domain-like protein 709 (MLKL) in astrocytes, followed by astroglial necroptosis around the lesion. This effect is likely 710 mediated through astroglial TLR4/MyD88 signaling, since astroglial MyD88 antagonism 711 alleviates M1 microglia/macrophage-induced death of astrocytes During infectious diseases, the major 724 contribution of astroglial TLR signaling is the host defense and the elimination of pathogens by 725 mounting an anti-viral and pro-inflammatory response. When persistent, the inflammatory attenuate the harmful ones Therefore, it is important to investigate In neurodegenerative diseases, pathogenic proteins that form aggregates induce promote the pro-inflammatory response of astrocytes. 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TLR signaling also promotes the production 1667 and release of pro These inflammatory responses can help the clearance of the pathogen but also cause 1669 degeneration and dysfunction of CNS cells. Astrocytes can also store, replicate, and 1670 disseminate viruses to the other CNS cells Aβ activates astrocytes through TLR4 signaling, 1677 induces the production of neurotoxic mediators, and causes neuronal death. α-syn is primarily 1678 released by neurons in pathological conditions. In the early stage of PD and other α-1679 synucleinopathies, astrocytes take up extracellular α-syn through endocytosis, which is 1680 mediated by TLR2, but not TLR4. However, the mechanisms of TLR2-mediated internalization 1681 of α-syn are not known. Excessive α-syn upregulates the expression of astroglial TLR2 and TLR4, 1682 activates TLR2 and TLR4 signaling, and promotes astrocyte-mediated neuroinflammation 1683 through the production of inflammatory mediators A schematic summary of the mechanisms by which astroglial TLRs contribute to CNS 1688 injury. Following traumatic brain and spinal cord injury, cells and tissue at the affected site are 1689 progressively damaged. Stressed and necrotic cells release endogenous ligands of TLRs This leads to the production of pro-inflammatory mediators, which further 1692 exacerbate the tissue damage and neuroinflammation. In addition, the activation of astroglial 1693 TLR4 enhances the expression of AQP4 and astrocyte swelling by mechanisms that remain 1694 elusive. Moreover, astroglial TLR9 regulates astrocyte proliferation during pathological 1695 conditions through the TLR9-MAPK pathway. 1696 1697 1698 1699 Reduction of viral permissiveness and replication