Microbiota-Inducible Innate Immune Siderophore Binding Protein Lipocalin 2 Is Critical for Intestinal Homeostasis

详细信息    查看全文

• 作者：Vishal Singh¹ ; ^&lowast ; ; Beng San Yeoh¹ ; ^&lowast ; ; Benoit Chassaing² ; Benyue Zhang² ; Piu Saha¹ ; Xia Xiao¹ ; Deepika Awasthi³ ; Rangaiah Shashidharamurthy⁴ ; Madhu Dikshit³ ; Andrew Gewirtz² ; Matam Vijay-Kumar¹ ; ⁵ ; ^{mvk13@psu.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Gut Microbiota ; Innate Immunity ; Germ-Free Mice ; MyD88 ; Colitis ; NGAL ; Siderocalin ; Neutrophils ; IBD
• 刊名：CMGH Cellular and Molecular Gastroenterology and Hepatology
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：2
• 期：4
• 页码：482-498.e6
• 全文大小：6874 K

文摘

Lipocalin 2 (Lcn2) is a multifunctional innate immune protein whose expression closely correlates with the extent of intestinal inflammation. However, whether Lcn2 plays a role in the pathogenesis of gut inflammation is unknown. Herein, we investigated the extent to which Lcn2 regulates inflammation and gut bacterial dysbiosis in mouse models of IBD.

Methods

Lcn2 expression was monitored in murine colitis models and upon microbiota ablation/restoration. Wild-type (WT) and Lcn2 knockout (Lcn2KO) mice were analyzed for gut bacterial load, composition by 16S ribosomal RNA gene pyrosequencing, and their colitogenic potential by co-housing with interleukin (Il)10KO mice. Acute (dextran sodium sulfate) and chronic (IL10R neutralization and T-cell adoptive transfer) colitis were induced in WT and Lcn2KO mice with or without antibiotics.

Results

Lcn2 expression was dramatically induced on inflammation and was dependent on the presence of a gut microbiota and MyD88 signaling. Use of bone marrow–chimeric mice showed that nonimmune cells are the major contributors of circulating Lcn2. Lcn2KO mice showed increased levels of entA-expressing gut bacteria burden, and, moreover, a broadly distinct bacterial community relative to WT littermates. Lcn2KO mice developed highly colitogenic T cells and showed exacerbated colitis on exposure to DSS or neutralization of IL10. Such exacerbated colitis could be prevented by antibiotic treatment. Moreover, exposure to the microbiota of Lcn2KO mice, via cohousing, resulted in severe colitis in Il10KO mice.

Conclusions

Lcn2 is a bacterially induced, MyD88-dependent protein that plays an important role in gut homeostasis and a pivotal role on challenge. Hence, therapeutic manipulation of Lcn2 levels may provide a strategy to help manage diseases driven by alteration of the gut microbiota.