Abstract
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 p38α 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 p38α contributes to acute and persistent inflammatory responses induced by a focal TBI. We generated conditional cell-specific knockout of p38α in microglia using a CX3CR1 Cre-lox system, subjected the p38α 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 p38α 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 p38α in propagation of a chronic and potentially neurotoxic pro-inflammatory environment in the brain following TBI.
Highlights
Following Traumatic brain injury (TBI), the innate immune system is activated to induce the recruitment of microglia to the site of injury [1, 2], followed by the subsequent recruitment and infiltration of multiple waves of systemic immune mediators [3,4,5,6]
We tested if microglia p38α is a significant contributor to TBI-induced neuroinflammatory responses, including the production of pro-inflammatory cytokines and recruitment of peripheral monocytes into the brain
Microglial p38α knockout mitigates acute neuroinflammatory responses to TBI We validated the tissue restriction of the CX3CR1CreERT2 [19] line by crossing them to the Ai9 reporter line, inducing recombination with a 28-day induction with tamoxifen chow, and using a 28-day washout period on standard chow to allow peripheral mononuclear cells to be replaced with non-recombined cells
Summary
Following TBI, the innate immune system is activated to induce the recruitment of microglia to the site of injury [1, 2], followed by the subsequent recruitment and infiltration of multiple waves of systemic immune mediators [3,4,5,6]. These conserved tissue responses [7] are geared to protect and repair the brain from further injury. We report here that loss of p38α in microglia significantly reduces TBI-induced neuroinflammatory responses at both acute (1-day) and subacute (7-day) time points after injury
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