Sterile Neuroinflammation and Strategies for Therapeutic Intervention

Figure 4

Mechanisms of glial cell activation in response to damage signals. Sterile neuroinflammatory conditions are characterized by the accumulation of misfolded and aggregated proteins in the brain. These DAMPs are released from different subcellular components of the damaged neurons, which trigger respective PRRs leading to downstream activation of proinflammatory cascades and enhancing effects of initial inflammatory insult. Activation of PRRs, primarily TLR2, TLR4, TLR9, and RAGE, converge largely into NF-κB activation, promoting cell death and/or contributing to neuroinflammatory/neurodegenerative mechanisms. These pathways, including P2XR, jointly work with multiprotein inflammasome complex (NLRs) that assists the generation of mature cytokines from proforms via the activation of caspase-1. TLR, toll-like receptor; RAGE, receptor for advanced glycation end products; NLR, nod-like receptor; P2XR, ATP-gated purinergic P2 receptors; MyD88, myeloid differentiation primary response gene (88); MAL, MyD88-adapter-like; TRIF, TIR-domain-containing adapter-inducing interferon-β; TRAM, TRIF-related adaptor molecule; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-kappa B; IL, interleukin.