Selective deletion of p38alpha MAPK in microglia mitigates neuroinflammatory responses to traumatic brain injury in mice
Josh Morganti, Linda Van Eldik
Introduction: Traumatic brain injury (TBI) is a significant cause of morbidity and mortality in the United States 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 p38a MAPK signaling pathway in microglia is a key contributor to inflammatory responses to diverse disease-relevant stressors and injury conditions.
Objective: Therefore, we tested whether microglia p38a contributes to acute and persistent inflammatory responses induced by a focal TBI.
Methods: We generated conditional cell-specific knockout of p38a in microglia using a CX3CR1 Cre-lox system, subjected the p38a 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.
Results: We found that deletion of p38a selectively in microglia was sufficient to attenuate multiple pro-inflammatory responses following TBI, notably reducing proinflammatory cytokine/ chemokine production and recruitment of inflammatory monocytes into the brain, and preventing the persistent microglial morphological activation.
Conclusions: These data provide strong evidence supporting a role for microglial p38a in propagation of a chronic and potentially neurotoxic proinflammatory environment in the brain following TBI.