Burn injury induces systemic inflammation and neuroinflammation with neurobehavioral sequalae in mice.

Abstract

BACKGROUND: Burn injury (BI) is one of the most devastating traumas, causing acute and long-term immune dysregulation and organ dysfunction. BI, by polygenic pathways, affects the central nervous system, which is manifested as chronic neurological dysfunction that extends well beyond complete wound healing. In this study, we examined BI-induced systemic inflammation and brain neuroinflammation and their impact on neurobehavior in mice. METHODS: Male C57BL/6 J mice were subjected to BI. Cytokine array and enzyme-linked immunosorbent assay were utilized to evaluate cytokine levels in the serum and brain, respectively. Tissue metabolism disturbance was assessed using targeted metabolomic analyses. Spleen monocytes/macrophages and brain microglia/macrophages were analyzed using flow cytometry analyses. Neurobehavioral changes after BI were assessed using a battery of behavioral tests. RESULTS: Systemic inflammation extended to the recovery phase after BI. Using cytokine array with 111 targets, we found that the levels of 19 circulating pro-inflammatory cytokines/chemokines were increased at 14 days after BI, including TNFα (30%) and M-CSF (19%). In the spleen, the number of monocytes/macrophages increased from 5% to ∼35% in BI mice. Concurrently, the levels of anti-inflammatory mediators, 3-indolepropoinc acid and indolelactic acid, were diminished after BI. Brain microgliosis and macrophage infiltration, together with disturbed metabolic homeostasis, were observed in BI mice. In the hippocampus, IL-6 level was elevated after BI. BI mice exhibited persistent pain, anxiety, and depressive-like behavior, and cognitive impairment when examined at 30 days after injury by which time the burn wounds had healed. CONCLUSIONS: In burn-injured mice, brain neuroinflammation and disrupted brain metabolic switch were concomitant with systemic inflammation. Mice exhibited neurobehavioral changes even after burn wounds had healed.