title: Severe neutrophil-dominated inflammation and enhanced myelopoiesis in IL-33-overexpressing CMV/IL33 mice.
abstract: IL-33 is a cytokine of the IL-1 family, which signals through the ST2 receptor. Previous studies emphasized a role for IL-33 in shaping innate and adaptive immune responses. IL-33 was also reported to modulate myelopoiesis and myeloid cell activity. In this article, we describe IL-33-overexpressing CMV/IL33 and LysM/IL33 mice, which display an inflammatory phenotype associated with growth retardation and paw swelling. The phenotype of CMV/IL33 mice is dependent on activation of the ST2 receptor and is characterized by extensive neutrophil infiltration into different organs, including the paws. Local or systemic levels of proinflammatory mediators such as IL-1β, Cxcl-1, G-CSF, and IL-6 are increased. CMV/IL-33 mice also suffer from anemia, thrombocytosis, and a marked dysregulation of myelopoiesis, leading to an important increase in myeloid cell production or accumulation in bone marrow (BM), spleen, and peripheral blood. Consistently, recombinant IL-33 induced proliferation of myeloid lineage cells in BM-derived granulocyte cultures, whereas IL-33 knockout mice exhibited minor deficiencies in spleen and BM myeloid cell populations. Our observations reveal a neutrophil-dominated inflammatory phenotype in IL-33-overexpressing CMV/IL33 and LysM/IL33 mice, and highlight important regulatory effects of IL-33 on myelopoiesis in vitro and in vivo, where excessive IL-33 signaling can translate into the occurrence of a myeloproliferative disorder.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine Specialties, University Hospital, 1211 Geneva 4, Switzerland; Department of Pathology-Immunology, University of Geneva School of Medicine, 1211 Geneva 4, Switzerland;
authors.forename: Dominique
authors.initials: D
authors.lastname: Talabot-Ayer
authors.affiliation: Division of Rheumatology, Department of Internal Medicine Specialties, University Hospital, 1211 Geneva 4, Switzerland; Department of Pathology-Immunology, University of Geneva School of Medicine, 1211 Geneva 4, Switzerland;
authors.forename: Praxedis
authors.initials: P
authors.lastname: Martin
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva School of Medicine, 1211 Geneva 4, Switzerland; and.
authors.forename: Christian
authors.initials: C
authors.lastname: Vesin
authors.affiliation: Novartis Pharma AG, 4056 Basel, Switzerland.
authors.forename: Christian Alexander
authors.initials: CA
authors.lastname: Seemayer
authors.affiliation: Division of Rheumatology, Department of Internal Medicine Specialties, University Hospital, 1211 Geneva 4, Switzerland; Department of Pathology-Immunology, University of Geneva School of Medicine, 1211 Geneva 4, Switzerland;
authors.forename: Solenne
authors.initials: S
authors.lastname: Vigne
authors.affiliation: Division of Rheumatology, Department of Internal Medicine Specialties, University Hospital, 1211 Geneva 4, Switzerland; Department of Pathology-Immunology, University of Geneva School of Medicine, 1211 Geneva 4, Switzerland;
authors.forename: Cem
authors.initials: C
authors.lastname: Gabay
authors.affiliation: Division of Rheumatology, Department of Internal Medicine Specialties, University Hospital, 1211 Geneva 4, Switzerland; Department of Pathology-Immunology, University of Geneva School of Medicine, 1211 Geneva 4, Switzerland; Gaby.Palmer@unige.ch.
authors.forename: Gaby
authors.initials: G
authors.lastname: Palmer
mesh_terms: D000740:Anemia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000818:Animals; D054360:Chemokine CXCL1 / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D000067596:Interleukin-33; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D038042:Myelopoiesis / Q000235:genetics / Q000276:immunology*; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013922:Thrombocytosis / Q000235:genetics / Q000276:immunology / Q000473:pathology
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; C587672:IL1B protein, mouse; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D053583:Interleukin-1beta; D000067596:Interleukin-33; D015850:Interleukin-6; D007378:Interleukins; D018123:Receptors, Interleukin; D016179:Granulocyte Colony-Stimulating Factor