Figure 1.

Glial immune interactions. Following ischemic-stroke signaling, mediators trigger glial and immune cell responses leading to inhibition or stimulation of neuronal cell death. These mediators include PAMPs, LPS, DAMPs, and cytokines: IL-4, IL-13, IL-10, IL-15, IL-1α, IFNγ, TNF-α, C1q, and IL-2. When microglia are activated by PAMPs or DAMPs, they change from a resting state to anti-inflammatory state (M2) or pro-inflammatory state (M1), respectively. Microglia in the M1 state can activate resting astrocytes causing their phenotypic shift into reactive astrocytes, resulting in neuronal cell death and exacerbating infarct damage. Microglia in the resting state which express PD-L1 can inhibit CD8⁺ T-cells by binding to their PD-1 receptor. Activation of astrocytes post-ischemic stroke leads to trans-presentation of IL-15, NK cells, and CD8⁺ T-cells which facilitate neuronal cell death. Monocyte activation following infarction leads to a dominant M2 microglial/monocyte phenotype resulting in the release of anti-inflammatory cytokines. Helper T-cells (Th1), IL-2, IFNγ, glutamate clearance, and mast cells in the brain have been shown to play neuroprotective roles to inhibit damaging effects of ischemic stroke. Green arrows represent stimulation. Lines with blunted ends (red) represent inhibition. The dashed red line represents inhibition of the PD-L1: PD-1 pathway only. See text for details. CCR2: CC chemokine receptor 2; PAMPs: pathogen-associated molecular patterns; LPS: lipopolysaccharides; DAMPs: damage-associated molecular patterns; IL-4: interleukin 4; IL-13: interleukin 13; IL-10: interleukin 10; IL-15: interleukin 15; IL-1α: interleukin 1 alpha; IFNγ: interferon gamma; TNF-α: tumor necrotic factor-alpha; C1q: complement component 1q; IL-2: interleukin 2; PD-L1: programmed death-ligand 1; PD-1: programmed death-1; NK: natural killer; CD: cluster of differentiation. (A color version of this figure is available in the online journal.)