Dysregulated hematopoietic stem and progenitor cell activity promotes interleukin-23-driven chronic intestinal inflammation

Immunity. 2012 Dec 14;37(6):1116-29. doi: 10.1016/j.immuni.2012.08.025. Epub 2012 Nov 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / metabolism
  • Cell Lineage
  • Cell Proliferation
  • Colitis / chemically induced
  • Colitis / immunology*
  • Colitis / metabolism*
  • Disease Models, Animal
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Hematopoiesis, Extramedullary
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism*
  • Interferon-gamma / metabolism
  • Interferon-gamma / pharmacology
  • Interleukin-23 / metabolism
  • Interleukin-23 / physiology*
  • Intestinal Mucosa / pathology
  • Intestinal Mucosa / physiology
  • Mice
  • Mice, Knockout
  • Spleen / physiology


  • Interleukin-23
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor