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. 2023 Jan 26;14:1097606. doi: 10.3389/fnagi.2022.1097606

Figure 1.

Figure 1

(A) Pathogenic model for Perioperative Neurocognitive Disorder in Mice. Peripheral trauma releases the alarmin HMGB1 which binds to pattern recognition receptors (PRRs) on circulating CCR2-expressing bone marrow-derived monocytes (BM-DMs) to transduce peripheral inflammation by translocating the transcription factor NF-kB into the nucleus and upregulating the synthesis and release of pro-inflammatory cytokines. High cytokine levels disrupt the blood brain barrier permitting entry of cytokines and BM-DMs into the hippocampus attracted by the chemokine MCP-1. Resident microglia become activated and, together with BM-DMs, cause further release of cytokines (including IL-6) that signal through transduction pathways to disrupt long-term potentiation (LTP). (B) IL-6 signaling: In classic signaling circulating IL-6 binds to membrane-bound receptor, IL-6Ra, resulting in dimerization of the transduction component, gp130, which triggers intracellular signaling. In trans-signaling, the shed ectodomain of IL-6R, sIL-6R, binds to IL-6 and the resulting heteroduplex can trigger intracellular signaling by directly binding to the gp130 dimer in the absence of IL-6R. (Adapted from PMID: 28620096).