Double negative T cells promote surgery-induced neuroinflammation, microglial engulfment and cognitive dysfunction via the IL-17/CEBPβ/C3 pathway in adult mice

Abstract

CD3(+) CD4(-) CD8(-) double negative T cells (DNTs) manifest themselves in autoimmune diseases and associated inflammation. In the central nervous system, the increased presence of DNTs is associated with the progression of neurological conditions and brain injury. Active DNTs that produce IL-17 have been regarded as a pro-inflammatory phenotype. The IL-17 signaling pathway mediates neuroinflammatory responses by inducing glial activation and producing inflammatory factors. Neuroinflammation is considered integral to the pathogenesis of perioperative neurocognitive disorders (PNDs), commonly developed after surgery in susceptible patients. We and others have demonstrated a significant role for complement C3 in surgery-induced neuroinflammation and cognitive impairment but the regulatory mechanisms for this remain unexplored. We hypothesized that surgery induces DNT infiltration into the CNS that in turn upregulates complement C3 expression and this causes changes that contribute to cognitive impairment. Using an adult murine abdominal surgery model, we investigated perioperative changes in cognitive performance, quantifying the presence of T cell subsets and phenotype, IL-17 signaling pathway activation, glial cell activation and C3 expression in the brain. Postoperative IL-17 specific inhibitor GSK2981278 administration or preoperatively conditional CEBPβ knock-down by AAV9 viral vector were then applied to evaluate the effect of inhibiting IL-17 signaling pathway on postoperative C3 expression and cognitive performance. The results showed an increased hippocampus infiltration of DNTs with augmented IL-17 production, along with C3 upregulation and cognitive impairment. Both inhibition of IL-17 or knock-down of CEBPβ significantly suppressed C3 expression, synaptic engulfment by microglia and attenuated cognitive impairment. These findings indicate that DNTs promote postoperative neuroinflammation and cognitive impairment via the IL-17/CEBPβ/C3 pathway and targeting this IL-17 axis could be a potential therapeutic strategy to ameliorate postoperative neuroinflammation and cognitive impairment.

Keywords: Astrocyte; Double negative T cells; Interleukin 17; Microglia; Neuroinflammation; Perioperative cognitive disorders.