Immune Surveillance of the CNS following Infection and Injury

“A number of studies have demonstrated that purinergic receptor signaling plays an important role in CNS sterile injury responses [28–31].”

“This structure physically blocks infiltrating immune cells in an attempt to protect proximal uninjured tissue [101].”

“A number of studies have demonstrated that purinergic receptor signaling plays an important role in CNS sterile injury responses [28–31].”

“Specialized innate immune sentinel cells are stationed at each of these locations and are conveniently named: meningeal macrophages, perivascular macrophages, CP macrophages, and microglia, the resident macrophages of the CNS (Figure 1) [5–7].”

“Inflammasomes form oligomeric structures in the cytoplasm, recruit caspase 1, and facilitate the proteolytic cleavage of pro-IL-1b and pro-IL-18 into their secreted active forms [18].”

“Activated astrocytes upregulate glial fibrillary acid protein and form a dense physical barrier surrounding damaged CNS tissue referred to as the glial scar (Figure 2) [100].”

“Cytopathic viruses, for example, can alert the immune system through direct cellular damage and release of damage-associated molecular patterns (DAMPs) [17].”

“In fact, two recent studies uncovered that the CNS is directly connected to secondary cervical lymph nodes via a standard lymphatic drainage system that can promote the generation of peripheral immune responses [1,2].”

“Macrophages and microglia can both be skewed into different activation states defined primarily by expression of pro- and anti-inflammatory molecules [90].”

“For example, P2X4R and P2X7R are two commonly expressed purinergic receptors in the CNS, and their stimulation can promote inflammasome activation [32–34].”

“Repair of these demyelinated lesions is mediated by neural precursor cells (NPCs) that differentiate into oligodendrocyte precursor cells (OPCs), and, ultimately, mature myelinating oligodendrocytes [97].”

“Specialized innate immune sentinel cells are stationed at each of these locations and are conveniently named: meningeal macrophages, perivascular macrophages, CP macrophages, and microglia, the resident macrophages of the CNS (Figure 1) [5–7].”

“Most models of CNS injury such as traumatic brain injury (TBI) and spinal cord injury (SCI) induce two phases of damage: the primary mechanical injury (e.g., severing of spinal cord tissue) and a secondary injury phase propagated by neurotoxic mediators such as reactive oxygen species (ROS), excitatory glutamate, and…”

“While it is clear that macrophages exhibit a spectrum of phenotypes with regard to function and cytokine production, there is increasing evidence to indicate that the conversion of initially proinflammatory microglia/macrophages to an anti-inflammatory state is beneficial in a variety of CNS injury models [91].”

“Adenosine receptors are expressed by both CNS-resident cells as well as peripheral innate and adaptive immune cells [86,87].”

“Microglia are usually among the first responders to sterile injuries, and one of their primary roles is clearing debris and dead cells from the lesion site [57].”

“This can be accomplished by cytopathic and non-cytopathic effector mechanisms (Figure 2), which have been reviewed elsewhere [46,47].”

“Normally, pericytes cover the vascular endothelium, but after SCI a subset of pericytes detach from vessels, proliferate, and migrate to the core of the scar and actually outnumber astrocytes [103].”

“ATP can be liberated from dying cells or actively pumped out of intact cells via connexin or pannexin hemichannels, which serves as an inflammatory amplifier [26,27].”

“Inhibition of this acute response via transcranial purinergic receptor (P2Y6R) or connexin hemichannel blockade enhanced breakdown of the glia limitans and cortical cell death, suggesting that this early inflammatory response to focal brain injury is neuroprotective [21,31].”

“Depletion of monocytes/macrophages using CD11c diphtheria toxin receptor mice was shown to enhance microglial activation and reduce spontaneous recovery following SCI [82].”

“Recognition of CNS Pathogens by Pattern Recognition Receptors Most immune responses begin with pattern recognition receptors (PRRs) sensing pathogenassociated molecular patterns (PAMPs) via Toll-like receptors (TLRs), RIG-like receptors (RLRs), or Nod-like receptors (NLRs) [8].”

“ATP can be liberated from dying cells or actively pumped out of intact cells via connexin or pannexin hemichannels, which serves as an inflammatory amplifier [26,27].”

“first to arrive following injury, which was followed days later by ‘non-classical’ tissue-healing monocytes (Ly6C CX3CR1 CCR2) [38].”

“These data demonstrate how instructive IFN-I signaling can be in the virally infected CNS and provide a possible explanation for why so many neurotropic viruses have acquired strategies to block this important pathway [16].”

“This proinflammatory state is maintained by iron accumulation and the release of TNF-/ by macrophages [62].”

“Expression of the programmed death ligand 1 (PD-L1) on CNS APCs can aid in suppression of CD8 and CD4 T cells through engagement of the programmed death receptor 1 (PD-1) on pathogen-specific T cells (Figure 2) [77].”

“Using this model, it was demonstrated that CCR2 monocytes had no effect on the demyelination or remyelination process [63].”

“This can be accomplished by cytopathic and non-cytopathic effector mechanisms (Figure 2), which have been reviewed elsewhere [46,47].”

“For example, P2X4R and P2X7R are two commonly expressed purinergic receptors in the CNS, and their stimulation can promote inflammasome activation [32–34].”

“Two recent studies also demonstrated that TREM2 deficiency impeded the ability of microglia to clean up myelin debris in the cuprizone model of demyelination [69] and acquire b-amyloid in an animal model of Alzheimer's disease [70].”

“Adenosine receptors are expressed by both CNS-resident cells as well as peripheral innate and adaptive immune cells [86,87].”

“Although immune cell migration into the CNS is tightly regulated due to the blood–brain barrier (BBB) [3], there exist routes that peripheral leukocytes can utilize to enter the cerebral spinal fluid (CSF), choroid plexus (CP), meninges, perivascular spaces, and eventually parenchymal tissue (Figure 1) [4].”

“By contrast, blockade of this receptor following CCI or SCI decreased tissue pathology and improved recovery [35,36].”

“Many members of the TLR, RLR, and NLR families recognize certain damage molecules as well as PAMPs [9,17].”

“Upon oral ingestion, cuprizone induces oligodendrocyte death, and this toxin is commonly fed to rodents to induce acute demyelination, which is followed by remyelination after cuprizone is removed from the diet [64,65].”

“Using a rodent model of WNV infection, it was demonstrated that recruitment of innate cells and virusspecific T cells into the CNS is essential for viral control [40,41].”

“Upon oral ingestion, cuprizone induces oligodendrocyte death, and this toxin is commonly fed to rodents to induce acute demyelination, which is followed by remyelination after cuprizone is removed from the diet [64,65].”

“Following brain ischemia, microglia upregulate TREM2, and TREM2 / mice show reduced numbers of activated microglia, a larger infarct size, and decreased functional recovery [68].”

“For example, myelin-containing macrophages in multiple sclerosis lesions (a human demyelinating disease) are thought to possess anti-inflammatory functions [60].”

“The CP is an important route of entry into the CNS that is also used by T cells to gain access to the CSF and perivascular spaces where they can interact with antigen-presenting immune sentinels [4,39].”

“In the case of a viral infection, RLR and TLR members will sense viral nucleic acids and induce expression of type I interferons (IFN-I) via interferon regulatory factor (IRF) activation [10,11].”

“In the case of a viral infection, RLR and TLR members will sense viral nucleic acids and induce expression of type I interferons (IFN-I) via interferon regulatory factor (IRF) activation [10,11].”

“During LCMV meningitis, CD8+ T cells can induce a pathogenic recruitment of innate myelomonocytic cells that break down cerebral blood vessels and contribute to fatal CNS edema (Figure 1, Movie S2) [54].”

“however, it is important to note that this protection sometimes has negative consequences [53].”

“The mechanisms used by T cells to control pathogens are varied and include granzymes, perforin, IFN-g, TNF-/, Fas ligand, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (Figure 2).”

“One day after SCI, injured axons are engulfed primarily by microglia [58].”

“This surface receptor binds to anionic ligands, such as LPS and dextran sulfate, which can promote phagocytosis of pathogens and CNS debris [66,67].”

“Lymphocytes are recruited to the CNS and accumulate in perivascular spaces due to high levels of CXCL12 expression; they then migrate into the parenchyma when CXCL12 levels decrease [42,43].”

“The major source of CXCL12 production in this model was found to be activated astrocytes [99].”

“TRAIL-mediated control of WNV is just one example of how T cells protect the CNS; 642 Trends in Immunology, October 2015, Vol. 36, No. 10 however, it is important to note that this protection sometimes has negative consequences [53].”

“For example, ischemic injury in mice lacking TGF-b signaling in astrocytes promoted increased monocyte recruitment to the CNS, elevated macrophage/microglia activation, and reduced recovery of motor function [102].”

“Interestingly, CD4 T cells promoted neuronal survival and better functional recovery even when transferred into MHC II / mice, demonstrating that T cells do not need to interact with cognate peptide–MHC II complexes to benefit the injured CNS [94].”

“damage cleanup and initiation of repair (Figures 1 and 2; Movies S1 and S3), although adaptive T and B cell responses can also participate [37].”

“Evaluation of P2X4R / mice following SCI revealed reduced myelomonocytic cell infiltration and tissue damage [34].”

“TLR4 has classically been associated with recognizing lipopolysaccharide (LPS) on Gram-negative bacteria, but was also shown to bind DAMPs, such as heat shock proteins (Hsp60, Hsp70), chromatin-associated high-mobility group protein B1 (HMGB1), fibronectin, and fibrinogen following tissue damage [22].”

“This finding was confirmed by another IVM study showing rare CD8 T cell division in the brain parenchyma after infection with the intracellular parasite, Toxoplasma gondii [45].”

“In fact, a delicate balance between effector CD4 T cells and Foxp3 Treg cells was found to be necessary for proper tissue repair in the injured spinal cord [93].”

“Following CCI, it was revealed that A2AR agonism was only neuroprotective at an early time point postinjury when glutamate levels were low [89].”

“Using a rodent model of WNV infection, it was demonstrated that recruitment of innate cells and virusspecific T cells into the CNS is essential for viral control [40,41].”

“IL-1b is a key regulator in this process that can promote CXCL12 expression in cerebral microvasculature and restrict T cell movement into the parenchyma by promoting CXCR4-mediated T cell adhesion [42].”

“LCMV is a non-cytopathic arenavirus recognized by cytosolic RLRs, retinoic acid-inducible gene I (RIG-I), and melanoma-differentiation-associated gene 5 (MDA5) [15].”

“By contrast, blockade of this receptor following CCI or SCI decreased tissue pathology and improved recovery [35,36].”

“Following CCI, it was revealed that A2AR agonism was only neuroprotective at an early time point postinjury when glutamate levels were low [89].”

“These cells provide critical surveillance of the CNS under steady-state conditions and are the first cells to detect foreign pathogens or tissue damage and initiate an immunological intervention [6].”

“Early production of IFN-I is critical in controlling the spread of CNS viral infections and often promotes host survival [12].”

“Following CNS infection with neurotropic mouse hepatitis virus (MHV), delayed depletion of CD4 T cells did not alter virus-specific CD8 T cell recruitment into the CNS, but instead impaired their function (IFN-g, granzyme b production) and survival, resulting in uncontrolled viral titers [48].”

“In some cases, Treg-mediated immune suppression is beneficial, as in the case of WNV [72]; however, in other instances of CNS infection, where the pathogen is the main cause of tissue damage, this type of immunosuppression is detrimental [73].”

“This neuroprotective function of T cells is in stark contrast to the severe immunopathology induced by autoreactive CD4 T cells that traffic to the CNS during the development of diseases such as experimental autoimmune encephalomyelitis [95].”

“Interestingly, the AIM2 (but not the NLRP3) inflammasome was identified as the critical ASC-dependent sensor in this model, as survival and production of proinflammatory cytokines/chemokines were both diminished in AIM2 / mice [20].”

“CD8 T cells can also release IFN-g onto virally infected neurons, promoting loss of dendrites and synapses [55].”

“The importance of the PD-L1/PD-1 pathway was examined in vivo using the MHV infection model [80,81].”

“A number of studies have demonstrated that purinergic receptor signaling plays an important role in CNS sterile injury responses [28–31].”

“Another study found that IFN-g could also induce upregulation of PD-L1 on cultured microglia, and both IFN-g-stimulated microglia and astrocytes were able to inhibit murine cytomegalovirus-specific CD8 T cell activity when cocultured together [79].”

“There is evidence that TLR4 has a role in the phagocytosis of degenerating axons, as microglia from TLR4 / (but not TLR3 / ) mice are significantly impaired in clearing axonal debris in vitro and in vivo [59].”

“Importantly, Treg cells can be used therapeutically to dampen antiviral T cell responses to CNS infections, an effect that is mediated in the CNS-draining cervical lymph nodes [75,76].”

“Infection of IL-10 / mice with neuroadapted Sindbis virus resulted in an accelerated paralytic disease that was linked to an increased recruitment of pathogenic CD4 T cells expressing IFN-g (Th1) and IL-17 (Th17) [84].”

“A recent study of WNV revealed that mice deficient in TRAIL had significantly lower survival rates and elevated viral titers in the CNS, but not peripheral tissues [52].”

“Therapeutic administration of antiviral CD8 and CD4 T cells to mice persistently infected from birth with LCMV resulted in non-cytopathic clearance of virally infected microglia following conversion into CD11c antigen-presenting cells (APCs) (Movie S3) [56].”

“Direct injection of Hsp60 into the CSF also induced both neuronal and oligodendrocyte death through a mechanism dependent on TLR4 and MyD88 [25].”

“Paradoxically, both A2A receptor (A2AR) agonism and antagonism can reduce tissue damage and improve motor function following SCI [88].”

“CXCL12 is upregulated in demyelinated areas and OPCs express the CXCR4 chemokine receptor [98].”

“In the absence of IFN-I signaling and antiviral T cells, LCMV established widespread persistence throughout the CNS, but induced almost no gene expression, microglia activation, or recruitment of circulating myelomonocytic cells [14].”

“Detection of bacterial flagellin was necessary to induce expression of caspase 1 and promote subsequent processing of pro-IL-1b and pro-IL-18 [19].”

“For example, a recent IVM study showed that antiviral CD8 T cells preferentially divide in the virally infected meninges versus the parenchyma [44].”

“Following MHV infection of the CNS, depletion of Treg cells induced an exacerbated inflammatory response characterized by an enhanced infiltration of lymphocytes and increased apoptotic neurons, which was linked to the expansion of autoreactive CD4 T cells [74].”

“Resident microglia upregulate PD-L1 after Theiler's murine encephalomyelitis virus (TMEV) infection, which was demonstrated in vitro to depend on IL-6 and IFN-I signaling [78].”

“The importance of the PD-L1/PD-1 pathway was examined in vivo using the MHV infection model [80,81].”

“IL-10 can also suppress innate and adaptive immune cells following CNS infection [83–85].”

“IL-10 can also suppress innate and adaptive immune cells following CNS infection [83–85].”

“It is likely that CD4 T cells similarly maintain effector B cells in the infected CNS, and this may be linked in part to local production of IL-21 by Th cells [49–51].”

“It is likely that CD4 T cells similarly maintain effector B cells in the infected CNS, and this may be linked in part to local production of IL-21 by Th cells [49–51].”

“It is likely that CD4 T cells similarly maintain effector B cells in the infected CNS, and this may be linked in part to local production of IL-21 by Th cells [49–51].”

“Importantly, Treg cells can be used therapeutically to dampen antiviral T cell responses to CNS infections, an effect that is mediated in the CNS-draining cervical lymph nodes [75,76].”

“The innate and adaptive immune systems actively participate in CNS surveillance, which is critical for the maintenance of CNS homeostasis and can facilitate the resolution of infections, degeneration, and tissue damage [30].”