Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, Henan, China.
Department of Gastroenterology, Peking University Third Hospital, No. 49 Huayuan North Road, Beijing 100191, China.
Int Immunopharmacol. 2021 Aug;97:107804. doi: 10.1016/j.intimp.2021.107804. Epub 2021 May 29.
The function of A20 as a deubiquitinating enzyme in inflammatory diseases and autoimmune diseases has been reported, we therefore aimed to investigate the potential effects of A20 in macrophages and dextran sodium sulfate (DSS)-induced colitis mouse model. Colitis mouse model was induced by DSS treatment. Tnfaip3 mice were crossed with Lyz2-Cre mice to generate A20 myeloid cell-conditional knockout mice. The expression levels of indicated cytokines were analyzed by quantitative reverse transcriptase real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Phosphorylated and total protein levels in nuclear factor kappa B (NF-κB) signaling pathway were detected by Western blot. In the bone marrow of mice, A20 deficiency did not affect macrophage development. In bone marrow-derived macrophages (BMDMs) after lipopolysaccharide (LPS) treatment, A20 deficiency enhanced pro-inflammatory cytokine expression. A20 deficiency in macrophages led to severe symptoms of DSS-induced colitis in mice. A20 deficiency enhanced the NF-κB signaling pathway activity in BMDMs. The effects of A20 deficiency in DSS-induced colitis were suppressed by NF-κB pathway inhibition. A20/inhibitor of NF-κB kinase 2 (IKKβ)-double knockout mice were resistant to DSS-induced colitis. A20 suppresses pro-inflammatory cytokine expression in macrophages through the NF-κB signal pathway and alleviates the pathogenesis of DSS-induced colitis in mice.
A20 作为一种去泛素化酶在炎症性疾病和自身免疫性疾病中的功能已被报道，因此我们旨在研究 A20 在巨噬细胞中的潜在作用和葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠模型。通过 DSS 处理诱导结肠炎小鼠模型。将 Tnfaip3 小鼠与 Lyz2-Cre 小鼠杂交，生成 A20 骨髓细胞条件性敲除小鼠。通过定量逆转录实时聚合酶链反应和酶联免疫吸附试验分析指示细胞因子的表达水平。通过 Western blot 检测核因子 kappa B（NF-κB）信号通路中磷酸化和总蛋白水平。在小鼠骨髓中，A20 缺乏不影响巨噬细胞的发育。在脂多糖（LPS）处理后的骨髓来源的巨噬细胞（BMDMs）中，A20 缺乏增强了促炎细胞因子的表达。巨噬细胞中的 A20 缺乏导致 DSS 诱导的结肠炎小鼠出现严重症状。A20 缺乏增强了 BMDMs 中 NF-κB 信号通路的活性。NF-κB 通路抑制抑制了 A20 缺乏在 DSS 诱导的结肠炎中的作用。A20/抑制 NF-κB 激酶 2（IKKβ）双敲除小鼠对 DSS 诱导的结肠炎具有抗性。A20 通过 NF-κB 信号通路抑制巨噬细胞中促炎细胞因子的表达，减轻 DSS 诱导的结肠炎小鼠的发病机制。
