Phosphatase Shp2 exacerbates intestinal inflammation by disrupting macrophage responsiveness to interleukin-10
Phosphatase Shp2 exacerbates intestinal inflammation by disrupting macrophage responsiveness to interleukin-10
复制标题
磷酸酶 Shp2 通过破坏巨噬细胞对白细胞介素 10 的反应而加剧肠道炎症
DOI：
10.1084/jem.20181198
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发表时间：
2019-02-01
影响因子：
15.3
通讯作者：
Ke, Yuehai
中科院分区：
文献类型：
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作者：
Xiao, Peng;Zhang, Huilun;Ke, Yuehai
由激活的巨噬细胞产生的炎性细胞因子在炎症性肠病(IBD)的病理征象中起重要作用。白介素10(IL-10)是肠道内主要的抗炎细胞因子，其治疗IBD的疗效已被临床验证。然而，IL-10在肠道微环境中的功能如何调节仍不清楚，这在很大程度上阻碍了以IL-10为基础的治疗策略的进一步发展。在这里，我们发现IBD患者的结肠巨噬细胞和外周血单核细胞中磷酸酶Shp2的表达比健康对照组增加。巨噬细胞中Shp2缺乏可以保护小鼠免受结肠炎和结肠炎驱动的结肠癌的侵袭。从机制上讲，Shp2可以破坏人和小鼠巨噬细胞的IL-10-STAT3信号及其依赖的抗炎反应。此外，我们的研究还揭示了肿瘤坏死因子-α在Shp2中的诱导作用。总之，我们的工作确认Shp2是肠道免疫动态平衡的有害因子，并有望对未来开发IL-10免疫疗法治疗IBD有所帮助。
Inflammatory cytokines produced by activated macrophages largely contribute to the pathological signs of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is the predominant anti-inflammatory cytokine in the intestine, and its therapeutic efficacy for IBD has been clinically tested. Nevertheless, how the function of IL-10 is regulated in the intestinal microenvironment remains unknown, which largely hinders the further development of IL-10-based therapeutic strategies. Here, we found that the expression of phosphatase Shp2 was increased in colonic macrophages and blood monocytes from IBD patients compared with those from healthy controls. Shp2 deficiency in macrophages protects mice from colitis and colitis-driven colon cancer. Mechanistically, Shp2 disrupts IL-10-STAT3 signaling and its dependent anti-inflammatory response in human and mouse macrophages. Furthermore, a Shp2-inducing role of TNF-alpha is unveiled in our study. Collectively, our work identifies Shp2 as a detrimental factor for intestinal immune homeostasis and hopefully will be helpful in the future exploitation of IL-10 immunotherapy for IBD.