| First Author | Escós A | Year | 2023 |
| Journal | Elife | Volume | 12 |
| PubMed ID | 37458356 | Mgi Jnum | J:340397 |
| Mgi Id | MGI:7525763 | Doi | 10.7554/eLife.86200 |
| Citation | Escos A, et al. (2023) p38gamma and p38delta modulate innate immune response by regulating MEF2D activation. Elife 12 |
| abstractText | Evidence implicating p38gamma and p38delta (p38gamma/p38delta) in inflammation are mainly based on experiments using Mapk12/Mapk13-deficient (p38gamma/deltaKO) mice, which show low levels of TPL2, the kinase upstream of MKK1-ERK1/2 in myeloid cells. This could obscure p38gamma/p38delta roles, since TPL2 is essential for regulating inflammation. Here, we generated a Mapk12(D171A/D171A)/Mapk13(-/-) (p38gamma/deltaKIKO) mouse, expressing kinase-inactive p38gamma and lacking p38delta. This mouse exhibited normal TPL2 levels, making it an excellent tool to elucidate specific p38gamma/p38delta functions. p38gamma/deltaKIKO 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 p38gamma/deltaKIKO macrophages revealed that p38gamma/p38delta-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 p38gamma/p38delta. 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 p38gamma/p38delta govern innate immune responses by regulating MEF2D phosphorylation and transcriptional activity. |
