title: Donor interleukin-22 and host type I interferon signaling pathway participate in intestinal graft-versus-host disease via STAT1 activation and CXCL10.
abstract: Acute graft-versus-host disease (aGVHD) remains a major complication following allogeneic hematopoietic cell transplantation, limiting the success of this therapy. We previously reported that interleukin-22 (IL-22) participates to aGVHD development, but the underlying mechanisms of its contribution remain poorly understood. In this study, we analyzed the mechanism of the pathological function of IL-22 in intestinal aGVHD. Ex-vivo colon culture experiments indicated that IL-22 was able to induce Th1-like inflammation via signal transducer and activator of transcription factor-1 (STAT1) and CXCL10 induction in the presence of type I interferon (IFN). To evaluate a potential synergy between IL-22 and type I IFN in aGVHD, we transplanted recipient mice, either wild-type (WT) or type I IFN receptor deficient (IFNAR(-/-)), with bone marrow cells and WT or IL-22 deficient (IL-22(-/-)) T cells. We observed a decreased GVHD severity in IFNAR(-/-) recipient of IL-22(-/-) T cells, which was associated with a lower level of STAT1 activation and reduced CXCL10 expression in the large intestine. Finally, immunohistochemistry staining of STAT1 performed on gastrointestinal biopsies of 20 transplanted patients showed exacerbated STAT1 activation in gastrointestinal tissues of patients with aGVHD as compared with those without aGVHD. Thus, interfering with both IL-22 and type I IFN signaling may provide a novel approach to limit aGVHD.
authors.affiliation: INSERM UMR1098, Besançon, France.|Université de Bourgogne Franche-Comté, UMR 1098, SFR FED 4234, Besançon, France.|EFS Bourgogne Franche-Comté, UMR 1098, Besançon, France.
authors.forename: B
authors.initials: B
authors.lastname: Lamarthée
authors.affiliation: Centre de Recherche Saint-Antoine, INSERM UMRs938, Paris, France.|Université Pierre et Marie Curie, Paris, France.|Service d'Hématologie Clinique, Hôpital Saint-Antoine, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Malard
authors.affiliation: INSERM UMR1098, Besançon, France.|Université de Bourgogne Franche-Comté, UMR 1098, SFR FED 4234, Besançon, France.|EFS Bourgogne Franche-Comté, UMR 1098, Besançon, France.
authors.forename: C
authors.initials: C
authors.lastname: Gamonet
authors.affiliation: EA4273 Biometadys, Faculté de médecine, Université de Nantes, Nantes, France.|Service d'Anatomie et Cytologie Pathologique, CHU de Nantes, Nantes, France.
authors.forename: C
authors.initials: C
authors.lastname: Bossard
authors.affiliation: INSERM UMR1098, Besançon, France.|Université de Bourgogne Franche-Comté, UMR 1098, SFR FED 4234, Besançon, France.|EFS Bourgogne Franche-Comté, UMR 1098, Besançon, France.
authors.forename: M
authors.initials: M
authors.lastname: Couturier
authors.affiliation: Ludwig Institute for Cancer Research and Experimental Medicine Unit, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: J-C
authors.initials: JC
authors.lastname: Renauld
authors.affiliation: Centre de Recherche Saint-Antoine, INSERM UMRs938, Paris, France.|Université Pierre et Marie Curie, Paris, France.|Service d'Hématologie Clinique, Hôpital Saint-Antoine, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Mohty
authors.affiliation: INSERM UMR1098, Besançon, France.|Université de Bourgogne Franche-Comté, UMR 1098, SFR FED 4234, Besançon, France.|EFS Bourgogne Franche-Comté, UMR 1098, Besançon, France.
authors.forename: P
authors.initials: P
authors.lastname: Saas
authors.affiliation: INSERM UMR1098, Besançon, France.|Université de Bourgogne Franche-Comté, UMR 1098, SFR FED 4234, Besançon, France.|EFS Bourgogne Franche-Comté, UMR 1098, Besançon, France.
authors.forename: B
authors.initials: B
authors.lastname: Gaugler
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D016026:Bone Marrow Transplantation; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D019337:Hematologic Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D007420:Intestine, Large / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D014019:Tissue Donors; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation; D000097043:Interleukin-22
chemical_list: D054357:Chemokine CXCL10; D007370:Interferon Type I; D007378:Interleukins; D053633:Receptor, Interferon alpha-beta; D050794:STAT1 Transcription Factor; D000097043:Interleukin-22; C485433:Cxcl10 protein, mouse; C508032:Ifnar1 protein, mouse; C494080:Stat1 protein, mouse