Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
Proc Natl Acad Sci U S A. 2017 Oct 17;114(42):11027-11033. doi: 10.1073/pnas.1711395114. Epub 2017 Sep 25.
The mammalian intestine is colonized by trillions of bacteria that perform essential metabolic functions for their hosts. The mutualistic nature of this relationship depends on maintaining spatial segregation between these bacteria and the intestinal epithelial surface. This segregation is achieved in part by the presence of a dense mucus layer at the epithelial surface and by the production of antimicrobial proteins that are secreted by epithelial cells into the mucus layer. Here, we show that resistin-like molecule β (RELMβ) is a bactericidal protein that limits contact between Gram-negative bacteria and the colonic epithelial surface. Mouse and human RELMβ selectively killed Gram-negative bacteria by forming size-selective pores that permeabilized bacterial membranes. In mice lacking RELMβ, Proteobacteria were present in the inner mucus layer and invaded mucosal tissues. Another RELM family member, human resistin, was also bactericidal, suggesting that bactericidal activity is a conserved function of the RELM family. Our findings thus identify the RELM family as a unique family of bactericidal proteins and show that RELMβ promotes host-bacterial mutualism by regulating the spatial segregation between the microbiota and the intestinal epithelium.
哺乳动物的肠道中定植着数以万亿计的细菌，这些细菌为宿主执行着重要的代谢功能。这种共生关系的本质取决于这些细菌与肠道上皮表面之间保持空间上的隔离。这种隔离部分是通过上皮表面存在致密的黏液层以及上皮细胞分泌到黏液层中的抗菌蛋白来实现的。在这里，我们表明抵抗素样分子β（RELMβ）是一种杀菌蛋白，它限制了革兰氏阴性菌与结肠上皮表面的接触。小鼠和人 RELMβ 通过形成大小选择性的孔选择性地杀死革兰氏阴性菌，这些孔可以使细菌膜通透性增加。在缺乏 RELMβ 的小鼠中，变形菌存在于内层黏液层并侵袭黏膜组织。人类抵抗素等另一种 RELM 家族成员也具有杀菌作用，这表明杀菌活性是 RELM 家族的一个保守功能。因此，我们的研究结果将 RELM 家族确定为一种独特的杀菌蛋白家族，并表明 RELMβ 通过调节微生物群与肠道上皮之间的空间隔离来促进宿主-细菌共生关系。
