Defining the role of Interleukin-6 for the development of perioperative neurocognitive disorders: Evidence from clinical and preclinical studies - PubMed (original) (raw)
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Defining the role of Interleukin-6 for the development of perioperative neurocognitive disorders: Evidence from clinical and preclinical studies
Odmara L Barreto Chang et al. Front Aging Neurosci. 2023.
Abstract
For most, staying "mentally sharp" as they age is a very high priority that may be thwarted by the consequences of a postoperative complication unrelated to the disorder which necessitated the surgical intervention. Perioperative neurocognitive disorder (PND) is an overarching term for cognitive impairment in surgical patients, that includes conditions from delirium to dementia, affecting more than 7 million patients annually in the US, and which threatens both functional independence and life. Clinical trials and meta-analyses have identified the association between PNDs and increased perioperative levels of Interleukin-6 (IL-6), a pleiotropic cytokine that is both necessary and sufficient for postoperative memory decline in a preclinical model of PND. Recently, we reported that, in adult male wild-type mice subjected to tibial fracture under general anesthesia, IL-6 trans-signaling in hippocampal CA1 neurons mediates surgery-induced memory impairment. As there are no therapeutic options for preventing or reversing PNDs, patients and their caregivers, as well as the healthcare industry, endure staggering costs. Olamkicept, a highly selective IL-6 trans-signaling blocker has shown to be efficacious and safe in clinical trials involving patients with inflammatory bowel disease, another condition for which IL-6 trans-signaling is the mediating mechanism. Subject to a demonstration that olamkicept is effective in preventing cognitive impairment in vulnerable (aged and Alzheimer's Disease) preclinical PND models, clinical trials involving aged and/or cognitively impaired surgical patients should be undertaken to study olamkicept's utility for PNDs.
Keywords: Alzheimer’s disease; IL-6; IL-6 trans-signaling; Olamkicept; PND; POD; aging; neuroinflammation; perioperative neurocognitive disorder.
Copyright © 2023 Barreto Chang and Maze.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Figures
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).
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).
References
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