p38γ and p38δ modulate innate immune response by regulating MEF2D activation

• Published in: eLife Vol. 12
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 17.07.2023; eLife Sciences Publications, Ltd
• Subjects: Animals; Antibodies; Biochemistry and Chemical Biology; Bone marrow; Cytokines; Extracellular signal-regulated kinase; Fibroblasts; Gene expression; Immune response; Immunity, Innate; Immunology and Inflammation; Infections; Inflammation; Inflammatory bowel disease; Inflammatory diseases; Innate immunity; Kinases; Lipopolysaccharides; Macrophages; MAPK; MEF2D; Mice; Mitogen-Activated Protein Kinase 12 - genetics; Mitogen-Activated Protein Kinase 12 - metabolism; Mitogen-Activated Protein Kinase 13 - metabolism; Myeloid cells; Myocytes; p38γ; p38δ; Phosphorylation; Proteins; Proteomics; Sepsis; Septic shock; mouse; chemical biology; inflammation; biochemistry; MAPK; p38δ; MEF2D; immunology; p38γ; phosphorylation
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.86200

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.