title: IL-33 Drives Eosinophil Infiltration and Pathogenic Type 2 Helper T-Cell Immune Responses Leading to Chronic Experimental Ileitis.
abstract: Although a clear association has been established between IL-33 and inflammatory bowel disease, mechanistic studies to date, primarily using acute murine models of colitis, have yielded contradicting results, demonstrating both pathogenic and protective roles. We used a well-characterized, spontaneous model of inflammatory bowel disease [ie, SAMP1/YitFc (SAMP) mice] to investigate the role of IL-33 during chronic intestinal inflammation. Our results showed marked eosinophil infiltration into the gut mucosa with increased levels of eotaxins and type 2 helper T-cell (Th2) cytokines as disease progressed and became more severe, which could be reversed upon either eosinophil depletion or blockade of IL-33 signaling. Exogenous IL-33 administration recapitulated these effects in ilea of uninflamed (parental) control AKR/J mice. Human data supported these findings, showing colocalization and up-regulation of IL-33 and eosinophils in the colonic mucosa of inflammatory bowel disease patients versus noninflamed controls. Finally, colonization of commensal flora by fecal material transplantation into germ-free SAMP and the presence of the gut microbiome induced IL-33, subsequent eosinophil infiltration, and mounting of Th2 immune responses, leading to exacerbation of chronic intestinal inflammation characteristic of SAMP mice. These data demonstrate a pathogenic role for IL-33-mediated eosinophilia and activation of Th2 immunity in chronic intestinal inflammation that is dependent on the gut microbiome. Targeting IL-33 may represent a novel therapeutic approach to treat patients with inflammatory bowel disease.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio; Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese and Department of Biomedical Sciences, University of Milan, Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: De Salvo
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Wang
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio; Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese and Department of Biomedical Sciences, University of Milan, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Pastorelli
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mattioli
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Sara
authors.initials: S
authors.lastname: Omenetti
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Kristine A
authors.initials: KA
authors.lastname: Buela
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Saleem
authors.initials: S
authors.lastname: Chowdhry
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Rekha R
authors.initials: RR
authors.lastname: Garg
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Goodman
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Alex
authors.initials: A
authors.lastname: Rodriguez-Palacios
authors.affiliation: Inflammation Research, Amgen, Seattle, Washington.
authors.forename: Dirk E
authors.initials: DE
authors.lastname: Smith
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Derek W
authors.initials: DW
authors.lastname: Abbott
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Fabio
authors.initials: F
authors.lastname: Cominelli
authors.affiliation: Academic Department of Gastroenterology, Kapodistrian University of Athens and Laikon Hospital, Athens, Greece.
authors.forename: Giorgos
authors.initials: G
authors.lastname: Bamias
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Wei
authors.initials: W
authors.lastname: Xin
authors.affiliation: Division of Pulmonary Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Scottsdale, Arizona.
authors.forename: James J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese and Department of Biomedical Sciences, University of Milan, Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Vecchi
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio. Electronic address: theresa.pizarro@case.edu.
authors.forename: Theresa T
authors.initials: TT
authors.lastname: Pizarro
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000166:cytology*; D007079:Ileitis / Q000276:immunology / Q000473:pathology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D000067596:Interleukin-33 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D018418:Th2 Cells / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D016207:Cytokines; C506535:Il33 protein, mouse; D000067596:Interleukin-33