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Escós, Alejandra; Diaz-Mora, Ester; Pattison, Michael; Fajardo, Pilar; González-Romero, Diego; Risco, Ana; Martín-Gómez, José; Bonneil, Éric; Sonenberg, Nahum; Jafarnejad, Seyed Mehdi; Sanz-Ezquerro, Juan José; Ley, Steven C; Cuenda, Ana
eLife, 07/2023, Volume: 12Journal Article
Evidence implicating p38γ and p38δ (p38γ/p38δ) in inflammation are mainly based on experiments using deficient (p38γ/δKO) mice, which show low levels of TPL2, the kinase upstream of MKK1-ERK1/2 in myeloid cells. This could obscure p38γ/p38δ roles, since TPL2 is essential for regulating inflammation. Here we generated a / (p38γ/δKIKO) mouse, expressing kinase-inactive p38γ and lacking p38δ. This mouse exhibited normal TPL2 levels, making it an excellent tool to elucidate specific p38γ/p38δ functions. p38γ/δKIKO mice showed a reduced inflammatory response and less susceptibility to LPS-induced septic shock and infection than wild-type mice. Gene expression analyses in LPS-activated WT and p38γ/δKIKO macrophages revealed that p38γ/p38δ regulated numerous genes implicated in innate immune response. Additionally, phospho-proteomic analyses and kinase assays showed that the transcription factor myocyte enhancer factor-2D (MEF2D) was phosphorylated at Ser444 via p38γ/p38δ. Mutation of MEF2D Ser444 to the non-phosphorylatable residue Ala increased its transcriptional activity and the expression of and mRNA. These results suggest that p38γ/p38δ govern innate immune responses by regulating MEF2D phosphorylation and transcriptional activity.
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