Figure 3.

Interactions between CNS-resident cells and the immune system during CNS inflammation. T cell activation is induced by myelin autoantigen presentation via dendritic cells and leads to the production and secretion of proinflammatory cytokines such as GM-CSF and IL-17. These cytokines exert proinflammatory effects on CNS-resident glial cells that respond to them, such as microglia and astrocytes, and promote neurodegeneration. In response to proinflammatory cytokine signals, microglia and astrocytes cross talk through multiple cues. In both astrocytes and microglia, proinflammatory cytokine signaling activates the transcription factor NF-kB and downregulates expression of the transcription factor AHR. NF-kB also inhibits activation of the antioxidant transcription factor NRF2 in astrocytes. Consequently, microglia upregulate and secrete proinflammatory molecules including IL-1β, IL-1α, TNF-α, C1q, and VEGFB while downregulating expression of anti-inflammatory TGF-α. Astrocytes sense these cues through cell surface receptors (IL1R, TNFRs, FLT1, ERBB1, GM-CSFRs, IL-17R, IFNGRs) and induce the expression of pathogenic transcriptional cascades including XBP1 (activated by ER stress), MAFG, and MAT2A alongside other pathogenic molecules like sphingolipid-induced cPLA2/MAVS, and complement component C3. Once activated, pathogenic astrocytes can secrete proinflammatory molecules including GM-CSF and CCL2, which lead to the recruitment of proinflammatory monocytes and encephalitogenic T cells to further promote CNS inflammation. Microglia and astrocytes may also engage in physical interactions during CNS inflammation, yet prominent examples remain to be elucidated. IFN-γ is reported to suppress CNS inflammation in mice and may mediate these functions in astrocytes and microglia through as-yet undetermined mechanisms. Control of microglial and astrocyte activation in the CNS has been linked to molecules derived from the commensal flora such as short-chain fatty acids, tryptophan metabolites, and neurotransmitters. Please note, however, that dietary metabolites such as tryptophan can be produced by the host as well as the commensal flora. Abbreviations: AHR, aryl hydrocarbon receptor; CNS, central nervous system; cPLA2, cytosolic phospholipase A2; C3, complement component 3; ER, endoplasmic reticulum; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFNGR, interferon gamma receptor; NK, natural killer; SCFA, short-chain fatty acid; TNFR, tumor necrosis factor receptor; XBP1, X-box binding protein 1.