Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
J Immunol. 2013 Sep 1;191(5):2764-2770. doi: 10.4049/jimmunol.1300908. Epub 2013 Aug 5.
Intestinal infections by attaching and effacing (A/E) bacterial pathogens cause severe colitis and bloody diarrhea. Although p38α in intestinal epithelial cells (IEC) plays an important role in promoting protection against A/E bacteria by regulating T cell recruitment, its impact on immune responses remains unclear. In this study, we show that activation of p38α in T cells is critical for the clearance of the A/E pathogen Citrobacter rodentium. Mice deficient of p38α in T cells, but not in macrophages or dendritic cells, were impaired in clearing C. rodentium. Expression of inflammatory cytokines such as IFN-γ by p38α-deficient T cells was reduced, which further reduced the expression of inflammatory cytokines, chemokines, and antimicrobial peptide by IECs and led to reduced infiltration of T cells into the infected colon. Administration of IFN-γ activated the mucosal immunity to C. rodentium infection by increasing the expression of inflammation genes and the recruitment of T cells to the site of infection. Thus, p38α contributes to host defense against A/E pathogen infection by regulating the expression of inflammatory cytokines that activate host defense pathways in IECs.
黏附性和破坏型（A/E）细菌病原体引起的肠道感染会导致严重的结肠炎和血性腹泻。虽然肠上皮细胞（IEC）中的 p38α 在调节 T 细胞募集以促进对抗 A/E 细菌的保护方面发挥着重要作用，但它对免疫反应的影响尚不清楚。在这项研究中，我们表明 T 细胞中 p38α 的激活对于清除 A/E 病原体柠檬酸杆菌至关重要。缺乏 T 细胞中 p38α 的小鼠，但不缺乏巨噬细胞或树突状细胞，清除 C. rodentium 的能力受损。p38α 缺陷型 T 细胞表达的炎性细胞因子（如 IFN-γ）减少，这进一步降低了 IEC 中炎性细胞因子、趋化因子和抗菌肽的表达，并导致 T 细胞浸润感染的结肠减少。IFN-γ 的给药通过增加炎症基因的表达和 T 细胞向感染部位的募集，激活了针对 C. rodentium 感染的黏膜免疫。因此，p38α 通过调节激活 IEC 中宿主防御途径的炎性细胞因子的表达，有助于宿主抵御 A/E 病原体感染。
