title: The p38α MAPK regulates microglial responsiveness to diffuse traumatic brain injury.
abstract: Neuropathology after traumatic brain injury (TBI) is the result of both the immediate impact injury and secondary injury mechanisms. Unresolved post-traumatic glial activation is a secondary injury mechanism that contributes to a chronic state of neuroinflammation in both animal models of TBI and human head injury patients. We recently demonstrated, using in vitro models, that p38α MAPK signaling in microglia is a key event in promoting cytokine production in response to diverse disease-relevant stressors and subsequent inflammatory neuronal dysfunction. From these findings, we hypothesized that the p38α signaling pathway in microglia could be contributing to the secondary neuropathologic sequelae after a diffuse TBI. Mice where microglia were p38α-deficient (p38α KO) were protected against TBI-induced motor deficits and synaptic protein loss. In wild-type (WT) mice, diffuse TBI produced microglia morphological activation that lasted for at least 7 d; however, p38α KO mice failed to activate this response. Unexpectedly, we found that the peak of the early, acute phase cytokine and chemokine levels was increased in injured p38α KO mice compared with injured WT mice. The increased cytokine levels in the p38α KO mice could not be accounted for by more infiltration of macrophages or neutrophils, or increased astrogliosis. By 7 d after injury, the cytokine and chemokine levels remained elevated in injured WT mice but not in p38α KO mice. Together, these data suggest that p38α balances the inflammatory response by acutely attenuating the early proinflammatory cytokine surge while perpetuating the chronic microglia activation after TBI.
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Bachstetter
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Rowe
authors.forename: Machi
authors.initials: M
authors.lastname: Kaneko
authors.forename: Danielle
authors.initials: D
authors.lastname: Goulding
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lifshitz
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Van Eldik
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000473:pathology*; D001930:Brain Injuries / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics*; D005911:Gliosis / Q000209:etiology / Q000235:genetics; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D048308:Mitogen-Activated Protein Kinase 14 / Q000172:deficiency / Q000378:metabolism*; D009043:Motor Activity; D009069:Movement Disorders / Q000209:etiology / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000473:pathology; D016037:Single-Blind Method; D013997:Time Factors
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D016207:Cytokines; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D048308:Mitogen-Activated Protein Kinase 14; D017493:Leukocyte Common Antigens
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