Abstract：
Immunoglobulin superfamily (IgSF) members are known for their role as glycoproteins expressed on the surface of immune cells, enabling protein-protein interactions to sense external signals during immune responses. However, the functions of immunoglobulins localized within subcellular compartments have been less explored. In this study, we identified an endoplasmic reticulum (ER)-localized immunoglobulin, IgSF member 6 (IgSF6), that regulates ER stress and the inflammatory response in intestinal macrophages. Igsf6 expression is sustained by microbiota and significantly upregulated upon bacterial infection. Mice lacking Igsf6 displayed resistance to Salmonella typhimurium challenge but increased susceptibility to dextran sulfate sodium-induced colitis. Mechanistically, deficiency of Igsf6 enhanced inositol-requiring enzyme 1α/-X-box binding protein 1 pathway, inflammatory response, and reactive oxygen species production leading to increased bactericidal activity of intestinal macrophages. Inhibition of reactive oxygen species or inositol-requiring enzyme 1α-X-box binding protein 1 pathway reduced the advantage of Igsf6 deficiency in bactericidal capacity. Together, our findings provide insight into the role of IgSF6 in intestinal macrophages that modulate the ER stress response and maintain intestinal homeostasis.
摘要：
免疫球蛋白超家族（IgSF）成员以其在免疫细胞表面表达的糖蛋白的作用而闻名。使蛋白质-蛋白质相互作用在免疫反应期间感知外部信号。然而,位于亚细胞区室中的免疫球蛋白的功能研究较少。在这项研究中,我们确定了一个ER定位的免疫球蛋白，IgSF成员6（IgSF6），调节内质网应激和肠巨噬细胞的炎症反应。Igsf6表达由微生物群维持并且在细菌感染时显著上调。缺乏Igsf6的小鼠表现出对S.Tyr攻击的抗性,但对葡聚糖硫酸钠(DSS)诱导的结肠炎的易感性增加。机械上,Igsf6缺陷增强了IRE1α/XBP1s途径，炎症反应和ROS产生，导致肠道巨噬细胞的杀菌活性增加。抑制ROS或IRE1α-XBP1途径降低了Igsf6缺乏在杀菌能力方面的优势。一起,我们的研究结果为IgSF6在肠道巨噬细胞中调节ER应激反应和维持肠道稳态的作用提供了见解.
