Neutrophils-derived Spink7 as one safeguard against experimental murine colitis.
Neutrophils-derived Spink7 as one safeguard against experimental murine colitis.
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DOI：
10.1016/j.bbadis.2021.166125
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发表时间：
2021-03
期刊：
影响因子：
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通讯作者：
Na Zhao;Guojian Wang;Shuang Long;Dengqun Liu;Jining Gao;Yang Xu;Cheng Wang;Aiping Wang
中科院分区：
文献类型：
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作者：
Na Zhao;Guojian Wang;Shuang Long;Dengqun Liu;Jining Gao;Yang Xu;Cheng Wang;Aiping Wang
不受控制的异常肠道免疫反应在引发炎症性肠病 (IBD) 中发挥着重要作用，但 IBD 期间调节肠道炎症的分子事件仍知之甚少。在这里，我们描述了一种控制实验性小鼠结肠炎炎症反应的内源性稳态模式。我们发现 Spink7（丝氨酸肽酶抑制剂，kazal 7 型）是人 SPINK7 的直系同源物，在葡聚糖硫酸钠 (DSS) 诱导的小鼠结肠炎模型中显着上调。 Spink7缺陷小鼠表现出高度易感实验性结肠炎，其特征是体重减轻增加、结肠长度缩短、疾病活动指数更高和结肠组织破坏增加。骨髓重建实验表明，免疫区室中 Spink7 的表达对其在结肠炎中的保护作用做出了主要贡献。更重要的是，中性粒细胞是实验性小鼠结肠炎中 Spink7 的主要来源。 Spink7 的缺失会导致结肠炎中多种趋化因子和细胞因子的产生增加。总之，这项研究确定了中性粒细胞衍生的内源性 Spink7 介导的趋化因子/细胞因子产生的控制是有助于结肠炎期间炎症消退的分子机制。
The uncontrolled abnormal intestinal immune responses play important role in eliciting inflammatory bowel disease (IBD), yet the molecular events regulating intestinal inflammation during IBD remain poorly understood. Here, we describe an endogenous, homeostatic pattern that controls inflammatory responses in experimental murine colitis. We show that Spink7 (serine peptidase inhibitor, kazal type 7), the ortholog of human SPINK7, is significantly upregulated in dextran sodium sulfate (DSS)-induced murine colitis model. Spink7-deficient mice showed highly susceptible to experimental colitis characterized by enhanced weight loss, shorter colon length, higher disease activity index and increased colonic tissue destruction. Bone marrow reconstitution experiments demonstrated that expression of Spink7 in the immune compartment makes main contribution to its protective role in colitis. What's more, neutrophils are the primary sources of Spink7 in experimental murine colitis. Loss of Spink7 leads to augmented productions of multiple chemokines and cytokines in colitis. In summary, this study identifies neutrophils-derived endogenous Spink7-mediated control of chemokines/cytokines production as a molecular mechanism contributing to inflammation resolution during colitis.