P38 alpha deficiency in macrophages ameliorates murine experimental colitis by regulating inflammation and immune process

Introduction: P38 alpha is a mitogen-activated protein kinase (MAPK) that mediates inflammatory responses. P38 alpha alterations have been associated with the inflammation-related diseases. However, the role of macrophages derived p38 alpha in dextran sulfate sodium (DSS)-induced murine experimental colitis remains unclear. Objectives: We characterized the role of macrophages-derived p38 alpha in DSS-induced colitis. Methods: The expression of macrophage-derived p38 alpha in human colitis and normal tissues was measured by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis. Macrophage-specific p38 alpha knockout (p38 alpha(Delta M phi)) and wild type (WT) mice administrated by 3% DSS were used to establish experimental colitis. The alterations in inflammatory cytokines, intestinal epithelial barrier, cell proliferation and cell apoptosis between p38 alpha(Delta M phi) and WT groups were determined by IHC, immunofluorescence (IF), TdT-mediated dUTP Nick-End Labeling (TUNEL) and Western blot analyses. The enriched pathways between p38 alpha(Delta M phi) and WT groups were identified by RNA-seq and KEGG analysis. SB203580 and BIRB796 as the p38 MAPK inhibitors were used to treat DSS-induced colitis. Results: p38 alpha was co-localized with CD68 in the cytoplasm and their co-expression indicated an increased level in colitis tissues as compared with the normal tissues. P38 alpha deficiency in macrophages was sufficient to suppress the exacerbated clinical symptoms and inflammation responses in experimental colitis, followed by reducing cytokine release, increasing MUC-2 and Claudin-2 secretion and promoting colonic mucosa repair. Further investigations validated that the immune process-related factors such as Lgals9, Rtp4, Ddx60, Nlrp1b, Hsh2d, Oas2 and Oas3 were upregulated in colon tissues from p38 alpha(Delta M phi) group as compared with the WT group. Inhibition of p38 MAPK attenuated DSS-induced colitis. Conclusion: Our findings demonstrated that p38 alpha deficiency in macrophages ameliorated murine experimental colitis by regulating inflammation and immune process.