巨噬细胞中 P38α 的缺失通过调节炎症和免疫过程改善了实验性结肠炎的小鼠模型。
P38α deficiency in macrophages ameliorates murine experimental colitis by regulating inflammation and immune process.
机构信息
Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Department of Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
出版信息
Pathol Res Pract. 2022 May;233:153881. doi: 10.1016/j.prp.2022.153881. Epub 2022 Apr 9.
INTRODUCTION
P38α is a mitogen-activated protein kinase (MAPK) that mediates inflammatory responses. P38α alterations have been associated with the inflammation-related diseases. However, the role of macrophages-derived p38α in dextran sulfate sodium (DSS)-induced murine experimental colitis remains unclear.
OBJECTIVES
We characterized the role of macrophages-derived p38α in DSS-induced colitis.
METHODS
The expression of macrophage-derived p38α in human colitis and normal tissues was measured by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis. Macrophage-specific p38α knockout (p38α) 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 p38α and WT groups were determined by IHC, immunofluorescence (IF), TdT-mediated dUTP Nick-End Labeling (TUNEL) and Western blot analyses. The enriched pathways between p38α 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
p38α 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. P38α 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 p38α group as compared with the WT group. Inhibition of p38 MAPK attenuated DSS-induced colitis.
CONCLUSION
Our findings demonstrated that p38α deficiency in macrophages ameliorated murine experimental colitis by regulating inflammation and immune process.
简介
P38α 是一种丝裂原活化蛋白激酶（MAPK），可介导炎症反应。P38α 的改变与炎症相关疾病有关。然而，巨噬细胞衍生的 p38α 在葡聚糖硫酸钠（DSS）诱导的小鼠实验性结肠炎中的作用尚不清楚。
目的
我们研究了巨噬细胞衍生的 p38α 在 DSS 诱导的结肠炎中的作用。
方法
通过免疫组织化学（IHC）和荧光原位杂交（FISH）分析测量人结肠炎和正常组织中巨噬细胞衍生的 p38α 的表达。使用 3% DSS 给药的巨噬细胞特异性 p38α 敲除（p38α）和野生型（WT）小鼠建立实验性结肠炎。通过 IHC、免疫荧光（IF）、末端转移酶介导的 dUTP 缺口末端标记（TUNEL）和 Western blot 分析测定 p38α 和 WT 组之间炎症细胞因子、肠上皮屏障、细胞增殖和细胞凋亡的变化。通过 RNA-seq 和 KEGG 分析鉴定 p38α 和 WT 组之间富集的途径。使用 p38 MAPK 抑制剂 SB203580 和 BIRB796 治疗 DSS 诱导的结肠炎。
结果
p38α 与 CD68 在细胞质中共定位，其共表达表明与正常组织相比，结肠炎组织中水平升高。巨噬细胞中 p38α 的缺失足以抑制实验性结肠炎中临床症状和炎症反应的加剧，随后减少细胞因子释放，增加 MUC-2 和 Claudin-2 分泌并促进结肠黏膜修复。进一步的研究证实，与 WT 组相比，p38α 组结肠组织中免疫过程相关因子如 Lgals9、Rtp4、Ddx60、Nlrp1b、Hsh2d、Oas2 和 Oas3 上调。抑制 p38 MAPK 可减轻 DSS 诱导的结肠炎。
结论
我们的研究结果表明，巨噬细胞中 p38α 的缺失通过调节炎症和免疫过程改善了小鼠实验性结肠炎。
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