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p38γ and p38δ modulate innate immune response by regulating MEF2D activation
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p38γ and p38δ modulate innate immune response by regulating MEF2D activation
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Journal Article
p38γ and p38δ modulate innate immune response by regulating MEF2D activation
2023
Overview
Evidence implicating p38γ and p38δ (p38γ/p38δ) in inflammation are mainly based on experiments using Mapk12/Mapk13 -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 Mapk12 D171A/D171A / Mapk13 −/− (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 lipopolysaccharide (LPS)-induced septic shock and Candida albicans infection than wild-type (WT) mice. Gene expression analyses in LPS-activated wild-type and p38γ/δKIKO macrophages revealed that p38γ/p38δ-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 p38γ/p38δ. 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 p38γ/p38δ govern innate immune responses by regulating MEF2D phosphorylation and transcriptional activity.
Publisher
eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
Subject
/ Biochemistry and Chemical Biology
/ Extracellular signal-regulated kinase
/ Kinases
/ MAPK
/ MEF2D
/ Mice
/ Mitogen-Activated Protein Kinase 12 - genetics
/ Mitogen-Activated Protein Kinase 12 - metabolism
/ Mitogen-Activated Protein Kinase 13 - metabolism
/ Myocytes
/ p38γ
/ p38δ
/ Proteins
/ Sepsis
