羟氯喹通过抑制NF-κB/NLRP3通路抑制M1型巨噬细胞极化减轻小鼠肠道炎症
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1.南京医科大学第一附属医院消化内科;2.徐州医科大学附属医院消化内科

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国家自然科学基金(82070568;82200582)通信作者(Corresponding author),E-mail: hjzhang06@163.com


Hydroxychloroquine ameliorates colitis in mice by inhibiting M1 macrophage polarization through NF-κB/NLRP3 signaling pathway
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Department of Gastroenterology,the First Affiliated Hospital of Nanjing Medical University

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The National Natural Science Foundation of China

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    摘要:

    目的:探讨羟氯喹(hydroxychloroquine,HCQ)对葡聚糖硫酸钠(dextran sulfate sodium salt,DSS)诱导的结肠炎模型鼠肠道炎症的影响及其抑制M1型巨噬细胞极化的相关机制。方法:C57BL/6小鼠随机分为3组:正常对照组(正常饮水+200μL纯水每日灌胃)、DSS组(自由饮用3.5% DSS溶液+ 200 μL纯水每日灌胃)、DSS+HCQ组【自由饮用3.5%DSS +200μL HCQ溶液(60mg/kg)每日灌胃】。造模期间通过观察小鼠粪便性状、测量体重进行疾病活动指数(disease activity index,DAI)评分。造模结束后测量小鼠结肠长度、结肠组织HE染色行组织病理学评分;提取结肠组织固有层单个核细胞(LPMC),流式细胞术检测M1型巨噬细胞比例。体外提取并诱导分化小鼠骨髓来源的巨噬细胞(BMDM),HCQ处理后,流式检测M1型巨噬细胞比例;蛋白质印迹法检测p-STAT1、IRF5、NF-κB/p65等表达水平。结果:HCQ可以减轻DSS诱导的小鼠肠道炎症并减少其结肠中M1型巨噬细胞比例。体外实验显示HCQ可抑制M1型巨噬细胞极化并同时抑制NF-κB p65信号通路及其下游NLRP3炎症小体的形成;利用NF-κB p65信号通路抑制剂PDTC可得到相似的结果。结论:羟氯喹可能通过抑制NF-κB/NLRP3信号通路抑制M1型巨噬细胞极化,从而减轻DSS诱导的小鼠肠道炎症。

    Abstract:

    : Objective: This study aims to explore the effect of hydroxychloroquine(HCQ)on dextran sulfate sodium salt(DSS)-induced colitis in mice and to reveal the underlying mechanisms of HCQ in the inhibition of M1 macrophages polarisation.Methods: All the C57BL/6 mice were randomly divided into 3 groups: the control group (common drinking water+200 μL pure water by gavage), DSS group (3.5% DSS drinking water+200 μL pure water by gavage) and DSS+HCQ group (3.5% DSS drinking water+200 μL HCQ of 60 mg/kg by gavage). The disease activity index(DAI)score was evaluated according to stool property and body weight change every day. The mice in each group were sacrificed after modeling experiment with the colon length measured. The colon tissues were stained with haematoxylin and eosin (H E) for histological score calculation. The colonic lamina propria mononuclear cells (LPMCs) were isolated and the proportion of M1 macrophages was measured by flow cytometry. In vitro, bone marrow-derived macrophages (BMDMs) were isolated and stimulated to induce M1 macrophages with the proportion measured by flow cytometry. The levels of p-STAT1, IRF5, NF-κB /p65,etc in the macrophages were detected by western blotting. Results: HCQ ameliorated DSS-induced colitis and significantly decreased the percentage of M1 macrophages in colonic LPMCs in DSS-induced colitis mice. In vitro, HCQ significantly repressed M1 polarisation. HCQ decreased the phosphorylation of NF-κB and the downstream of NLRP3 inflammasome formation in M1 macrophages. The similar results were observed with PDTC treatment (an inhibitor of NF-κB signaling). Conclusion: HCQ attenuated colonic inflammation in mice by supressing M1 macrophage polarization through the inhibition of NF-κB/NLRP3 signaling pathway.

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  • 收稿日期:2023-07-23
  • 最后修改日期:2023-08-18
  • 录用日期:2023-10-25
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