p38 & gamma; and p38 & delta; modulate innate immune response by regulating MEF2D activation

Evidence implicating p38? and p38d (p38?/p38d) in inflammation are mainly based on experiments using Mapk12/Mapk13-deficient (p38?/dKO) mice, which show low levels of TPL2, the kinase upstream of MKK1-ERK1/2 in myeloid cells. This could obscure p38?/p38d roles, since TPL2 is essential for regulating inflammation. Here, we generated a Mapk12(D171A/D171A)/Mapk13(-/-) (p38?/dKIKO) mouse, expressing kinase-inactive p38? and lacking p38d. This mouse exhibited normal TPL2 levels, making it an excellent tool to elucidate specific p38?/p38d functions. p38?/dKIKO mice showed a reduced inflammatory response and less susceptibility to lipopolysaccharide (LPS)-induced septic shock and Candida albicans infection than wild-type (WT) mice. Gene expression analyses in LPS-activated wild-type and p38?/dKIKO macrophages revealed that p38?/p38d-regulated numerous genes implicated in innate immune response. Additionally, phospho-proteomic analyses and in vitro kinase assays showed that the transcription factor myocyte enhancer factor-2D (MEF2D) was phosphorylated at Ser444 via p38?/p38d. Mutation of MEF2D Ser444 to the non-phosphorylatable residue Ala increased its transcriptional activity and the expression of Nos2 and Il1b mRNA. These results suggest that p38?/p38d govern innate immune responses by regulating MEF2D phosphorylation and transcriptional activity.