Roberts Morgan E, Bishop Jennifer L, Fan Xueling, Beer Jennifer L, Kum Winnie W S, Krebs Danielle L, Huang Morris, Gill Navkiran, Priatel John J, Finlay B Brett, Harder Kenneth W
Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada;
Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada; and.
J Immunol. 2014 Nov 15;193(10):5249-63. doi: 10.4049/jimmunol.1302832. Epub 2014 Oct 22.
The Lyn tyrosine kinase governs the development and function of various immune cells, and its dysregulation has been linked to malignancy and autoimmunity. Using models of chemically induced colitis and enteric infection, we show that Lyn plays a critical role in regulating the intestinal microbiota and inflammatory responses as well as protection from enteric pathogens. Lyn(-/-) mice were highly susceptible to dextran sulfate sodium (DSS) colitis, characterized by significant wasting, rectal bleeding, colonic pathology, and enhanced barrier permeability. Increased DSS susceptibility in Lyn(-/-) mice required the presence of T but not B cells and correlated with dysbiosis and increased IFN-γ(+) and/or IL-17(+) colonic T cells. This dysbiosis was characterized by an expansion of segmented filamentous bacteria, associated with altered intestinal production of IL-22 and IgA, and was transmissible to wild-type mice, resulting in increased susceptibility to DSS. Lyn deficiency also resulted in an inability to control infection by the enteric pathogens Salmonella enterica serovar Typhimurium and Citrobacter rodentium. Lyn(-/-) mice exhibited profound cecal inflammation, bacterial dissemination, and morbidity following S. Typhimurium challenge and greater colonic inflammation throughout the course of C. rodentium infection. These results identify Lyn as a key regulator of the mucosal immune system, governing pathophysiology in multiple models of intestinal disease.
Lyn酪氨酸激酶调控多种免疫细胞的发育和功能，其失调与恶性肿瘤和自身免疫性疾病相关。利用化学诱导性结肠炎和肠道感染模型，我们发现Lyn在调节肠道微生物群和炎症反应以及抵御肠道病原体方面发挥关键作用。Lyn基因敲除（Lyn(-/-)）小鼠对葡聚糖硫酸钠（DSS）诱导的结肠炎高度敏感，表现为明显消瘦、直肠出血、结肠病理改变以及屏障通透性增强。Lyn(-/-)小鼠对DSS易感性增加需要T细胞而非B细胞的存在，且与菌群失调以及结肠中IFN-γ(+)和/或IL-17(+) T细胞增多相关。这种菌群失调的特征是分节丝状菌扩张，伴有肠道IL-22和IgA产生改变，并且可传播给野生型小鼠，导致其对DSS易感性增加。Lyn缺陷还导致无法控制肠道病原体鼠伤寒沙门氏菌和啮齿柠檬酸杆菌的感染。Lyn(-/-)小鼠在受到鼠伤寒沙门氏菌攻击后出现严重的盲肠炎症、细菌播散和发病，在啮齿柠檬酸杆菌感染过程中整个结肠炎症更严重。这些结果表明Lyn是黏膜免疫系统的关键调节因子，在多种肠道疾病模型中调控病理生理过程。
