Microglia, the resident immune cells of the central nervous system (CNS), play a major role in
damage progression and tissue remodeling after acute CNS injury, including ischemic stroke
(IS) and spinal cord injury (SCI). Understanding the molecular mechanisms regulating
microglial responses to injury may thus reveal novel therapeutic targets to promote CNS repair.
Here, we investigated the role of microglial tumor necrosis factor receptor 2 (TNFR2), a
transmembrane receptor previously associated with pro-survival and neuroprotective
responses, in shaping the neuroinflammatory environment after CNS injury. By inducing
experimental IS and SCI in Cx3cr1CreER:Tnfrsf1bfl/fl mice, selectively lacking TNFR2 in
microglia, and corresponding Tnfrsf1bfl/fl littermate controls, we found that ablation of
microglial TNFR2 significantly reduces lesion size and pro-inflammatory cytokine levels, and
favors infiltration of leukocytes after injury. Interestingly, these effects were paralleled by
opposite sex-specific modifications of microglial reactivity, which was found to be limited in
female TNFR2-ablated mice compared to controls, whereas it was enhanced in males. In
addition, we show that TNFR2 protein levels in the cerebrospinal fluid (CSF) of human
subjects affected by IS and SCI, as well as healthy donors, significantly correlate with disease
stage and severity, representing a valuable tool to monitor the inflammatory response after
acute CNS injury. Hence, these results advance our understanding of the mechanisms
regulating microglia reactivity after acute CNS injury, aiding the development of sex- and
microglia-specific, personalized neuroregenerative strategies.
TidsskriftBrain, Behavior, and Immunity
Sider (fra-til)269-285
StatusUdgivet - feb. 2024