炎症
炎症性肠病
纤维化
基因敲除
白细胞介素17
免疫学
白细胞介素23
T细胞
流式细胞术
医学
FOXP3型
癌症研究
生物
免疫系统
病理
细胞凋亡
疾病
生物化学
作者
Cody Howe,Marina Chulkina,Ryan Syrcle,Christina McAninch,Steven McAninch,Irina V. Pinchuk,Ellen J. Beswick
摘要
Abstract Background CD4+ T cells contribute to chronic inflammation and fibrosis in inflammatory bowel disease (IBD), but the cellular mechanisms remain elusive. We have found that the mitogen-activated protein kinase 2 (MK2) pathway plays a major role in inflammation and overall pathology in IBD. Thus, here, we examined the role of MK2 in regulating CD4+ T cell responses in IBD models. Methods Interleukin-10 (IL-10) knockout (KO) mice treated with MK2 inhibitors (MK2i) and CD4-specific MK2 knockdown mice treated with chronic dextran sodium sulfate (DSS) treatments were used to examine inflammation and fibrosis by multiplex array, gene expression, flow cytometry, and histology. Human tissues were treated with MK2i to examine Th1 and Th17 markers. Results IL-10 KO mice treated with MK2i therapeutically showed significantly reduced interferon gamma (IFNγ) and interleukin-17A (IL-17A) and a significantly reduced number of IFNγ+ and IL-17A+ producing CD4+ T cells by flow cytometry. To investigate the direct role of MK2 in CD4+ T cells during IBD, we utilized CD4-specific MK2 knockdown mice in chronic DSS colitis. A decrease in colonic inflammation, IFNγ and IL-17, pro-fibrotic genes, and extracellular matrix deposition was observed in mice with MK2 knockdown in CD4+ T cells compared to control mice. Additionally, IL-17A and IFNγ directly regulated the expression of fibrosis genes in colon tissues. Conclusions The MK2 pathway regulates inflammatory CD4+ T cells and fibrosis in IBD models and is a potential therapeutic target.
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