title: Dysregulated hematopoietic stem and progenitor cell activity promotes interleukin-23-driven chronic intestinal inflammation.
abstract: In interleukin-23 (IL-23)-dependent colitis, there is excessive accumulation of short-lived neutrophils and inflammatory monocytes in the intestine. It is unknown whether this reflects changes in mature cell populations or whether the IL-23-driven colitogenic T cell program regulates upstream hematopoietic stem and progenitor cells (HSPC). Here we have shown dysregulation of hematopoiesis in colitis mediated by inflammatory cytokines. First, there was an interferon-gamma-dependent accumulation of proliferating hematopoietic stem cells in the bone marrow and spleen. Second, there was a strong skew toward granulocyte-monocyte progenitor (GMP) production at the expense of erythroid and lymphoid progenitors. Extramedullary hematopoiesis was also evident, and granulocyte macrophage-colony stimulating factor (GM-CSF) blockade reduced the accumulation of splenic and colonic GMPs, resulting in amelioration of colitis. Importantly, transfer of GMPs exacerbated colitis. These data identify HSPCs as a major target of the IL-23-driven inflammatory axis suggesting therapeutic strategies for the treatment of inflammatory bowel disease.
authors.affiliation: Translational Gastroenterology Unit, Experimental Medicine Division Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Thibault
authors.initials: T
authors.lastname: Griseri
authors.forename: Brent S
authors.initials: BS
authors.lastname: McKenzie
authors.forename: Chris
authors.initials: C
authors.lastname: Schiering
authors.forename: Fiona
authors.initials: F
authors.lastname: Powrie
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D019070:Cell Lineage; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006411:Hematopoiesis, Extramedullary; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D053759:Interleukin-23 / Q000378:metabolism / Q000502:physiology*; D007413:Intestinal Mucosa / Q000473:pathology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D013154:Spleen / Q000502:physiology
chemical_list: D053759:Interleukin-23; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor