title: Microbiota-inducible Innate Immune, Siderophore Binding Protein Lipocalin 2 is Critical for Intestinal Homeostasis.
abstract: OBJECTIVE
  Lipocalin 2 (Lcn2) is a multifunctional innate immune protein whose expression closely correlates with 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. WT andLcn2knockout (Lcn2KO) mice were analyzed for gut bacterial load, composition by 16S rRNA gene pyrosequencing and, their colitogenic potential by co-housing withIl-10KO mice. Acute (dextran sodium sulfate) and chronic (IL-10R neutralization and T-cell adoptive transfer) colitis was induced in WT andLcn2KO mice with or without antibiotics.
  
  
  RESULTS
  Lcn2 expression was dramatically induced upon inflammation and was dependent upon presence of a gut microbiota and MyD88 signaling. Use of bone-marrow chimeric mice revealed non-immune cells are the major contributors of circulating Lcn2.Lcn2KO mice exhibited elevated levels ofentA-expressing gut bacteria burden and, moreover, a broadly distinct bacterial community relative to WT littermates.Lcn2KO mice developed highly colitogenic T-cells and exhibited exacerbated colitis upon exposure to DSS or neutralization of IL-10. Such exacerbated colitis could be prevented by antibiotic treatment. Moreover, exposure to the microbiota ofLcn2KO mice, via cohousing, resulted in severe colitis inIl-10KO mice.
  
  
  CONCLUSIONS
  Lcn2 is a bacterially-induced, MyD88-dependent, protein that play an important role in gut homeostasis and a pivotal role upon challenge. Hence, therapeutic manipulation of Lcn2 levels may provide a strategy to help manage diseases driven by alteration of the gut microbiota.
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802.
authors.forename: Vishal
authors.initials: V
authors.lastname: Singh
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802.
authors.forename: Beng San
authors.initials: BS
authors.lastname: Yeoh
authors.affiliation: Center for Inflammation, Immunity & Infection, Institute of Biomedical Sciences, Georgia State University, Atlanta, GA 30303.
authors.forename: Benoit
authors.initials: B
authors.lastname: Chassaing
authors.affiliation: Center for Inflammation, Immunity & Infection, Institute of Biomedical Sciences, Georgia State University, Atlanta, GA 30303.
authors.forename: Benyue
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802.
authors.forename: Piu
authors.initials: P
authors.lastname: Saha
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802.
authors.forename: Xia
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow, 226031 India.
authors.forename: Deepika
authors.initials: D
authors.lastname: Awasthi
authors.affiliation: Department of Pharmaceutical Sciences, Philadelphia College of Osteopathic Medicine, Suwanee, Georgia 30024, USA.
authors.forename: Rangaiah
authors.initials: R
authors.lastname: Shashidharamurthy
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow, 226031 India.
authors.forename: Madhu
authors.initials: M
authors.lastname: Dikshit
authors.affiliation: Center for Inflammation, Immunity & Infection, Institute of Biomedical Sciences, Georgia State University, Atlanta, GA 30303.
authors.forename: Andrew
authors.initials: A
authors.lastname: Gewirtz
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802; Department of Medicine, The Pennsylvania State University Medical Center, Hershey, PA 17033.
authors.forename: Matam
authors.initials: M
authors.lastname: Vijay-Kumar
keywords: Colitis; Germ-free mice; Gut Microbiota; IBD; Innate Immunity; MyD88; NGAL; Neutrophils; Siderocalin