Defining the role of Interleukin-6 for the development of perioperative neurocognitive disorders: Evidence from clinical and preclinical studies

Figures

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  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).

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  Figure 2. IL-6 trans-signaling in CA1 hippocampal neurons produces postoperative memory impairment. (A) Adult male mice underwent training for trace fear-conditioning (TFC) prior to tibia fracture surgery. At 24 h mice were killed and samples harvested; separate cohorts underwent testing in TFC at 72 h. Postoperatively, hippocampal IL-6 levels (B) and CSF sIL-6R levels (C) rise significantly. (D) Freezing time in the TFC declines significantly in the surgical group indicating postoperative memory impairment. (E) The number of pSTAT3 + neurons (counterstained with NeuN) increased significantly after surgery indicating upregulated IL-6 signaling. Following depletion of gp130 in the CA1 region of the hippocampus with direct injection of a viral vector containing a cassette to knockdown gp130 in excitatory neurons, surgery no longer decreases freezing time (F) nor increases the number of pSTAT3+/Neun+ cells (G). Following administration of the selective IL-6 trans-signaling blocker, sgp130Fc, both postoperative freezing time (H) and the (I) number of pSTAT3 + neurons return to normal (Adapted from PMID: 36253222).