Deletion of p38 MAPK in microglia blunts trauma-induced inflammatory responses in mice

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality in the USA and other developed countries worldwide. Following the initial mechanical insult, the brain's primary innate immune effector, microglia, initiate inflammatory signaling cascades and pathophysiological responses that can lead to chronic neuroinflammation and neurodegenerative sequelae. The p38 MAPK signaling pathway in microglia is a key contributor to inflammatory responses to diverse disease-relevant stressors and injury conditions. Therefore, we tested here whether microglia p38 contributes to acute and persistent inflammatory responses induced by a focal TBI. We generated conditional cell-specific knockout of p38 in microglia using a CX3CR1 Cre-lox system, subjected the p38 knockout and wild-type mice to a controlled cortical impact TBI, and measured inflammatory responses at acute (1-day) and subacute (7-day) post-injury time points. We found that deletion of p38 in microglia only was sufficient to attenuate multiple pro-inflammatory responses following TBI, notably reducing pro-inflammatory cytokine/chemokine production and recruitment of inflammatory monocytes into the brain and preventing the persistent microglial morphological activation. These data provide strong evidence supporting a role for microglial p38 in propagation of a chronic and potentially neurotoxic pro-inflammatory environment in the brain following TBI.