Home LiteratureArticle Details
PMID: 23200826 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Immunity ·Vol. 37 ·No. 6 ·2012-12-14 ·Pages 1116-29

Griseri T, McKenzie BS, Schiering C, Powrie F

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.

MeSH Terms
Animals Bone Marrow Cells/metabolism Cell Lineage Cell Proliferation Colitis/chemically induced,immunology,metabolism Disease Models, Animal Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology Hematopoiesis, Extramedullary Hematopoietic Stem Cells/cytology,drug effects,metabolism Interferon-gamma/metabolism,pharmacology Interleukin-23/metabolism,physiology Intestinal Mucosa/pathology,physiology Mice Mice, Knockout Spleen/physiology
Chemicals
Interleukin-23 Interferon-gamma Granulocyte-Macrophage Colony-Stimulating Factor
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Griseri Thibault
Translational Gastroenterology Unit, Experimental Medicine Division Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
McKenzie Brent S
Schiering Chris
Powrie Fiona
References (42)
42 references, click to expand
  1. Neutrophils and immunity: challenges and opportunities.
    Nat Rev Immunol. 2006 Mar;6(3):173-82 PMID: 16498448
  2. A novel function of interleukin-10 promoting self-renewal of hematopoietic stem cells.
    Stem Cells. 2007 Jul;25(7):1814-22 PMID: 17464085
  3. Biology of hematopoietic stem cells and progenitors: implications for clinical application.
    Annu Rev Immunol. 2003;21:759-806 PMID: 12615892
  4. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells.
    Cell. 2005 Jul 1;121(7):1109-21 PMID: 15989959
  5. Mammalian target of rapamycin activation underlies HSC defects in autoimmune disease and inflammation in mice.
    J Clin Invest. 2010 Nov;120(11):4091-101 PMID: 20972332
  6. TGF-beta as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation.
    Blood. 2009 Feb 5;113(6):1250-6 PMID: 18945958
  7. OX40 is required for regulatory T cell-mediated control of colitis.
    J Exp Med. 2010 Apr 12;207(4):699-709 PMID: 20368580
  8. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells.
    Immunity. 1994 Oct;1(7):553-62 PMID: 7600284
  9. Interleukin-23 drives innate and T cell-mediated intestinal inflammation.
    J Exp Med. 2006 Oct 30;203(11):2473-83 PMID: 17030949
  10. Regulatory lymphocytes and intestinal inflammation.
    Annu Rev Immunol. 2009;27:313-38 PMID: 19302043
  11. The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF.
    Nat Immunol. 2011 Jun;12(6):568-75 PMID: 21516111
  12. Interleukin-23 drives intestinal inflammation through direct activity on T cells.
    Immunity. 2010 Aug 27;33(2):279-88 PMID: 20732640
  13. Identification of eosinophil lineage-committed progenitors in the murine bone marrow.
    J Exp Med. 2005 Jun 20;201(12):1891-7 PMID: 15955840
  14. Niche recycling through division-independent egress of hematopoietic stem cells.
    J Exp Med. 2009 Nov 23;206(12):2837-50 PMID: 19887396
  15. Demand-adapted regulation of early hematopoiesis in infection and inflammation.
    Blood. 2012 Mar 29;119(13):2991-3002 PMID: 22246037
  16. Neutrophil transepithelial migration and epithelial barrier function in IBD: potential targets for inhibiting neutrophil trafficking.
    Ann N Y Acad Sci. 2006 Aug;1072:276-87 PMID: 17057207
  17. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation.
    Nat Immunol. 2011 Jun;12(6):560-7 PMID: 21516112
  18. FoxP3+ regulatory T cells restrain splenic extramedullary myelopoiesis via suppression of hemopoietic cytokine-producing T cells.
    J Immunol. 2009 Nov 15;183(10):6377-86 PMID: 19890066
  19. Functional characterization of hematopoietic stem cells in the spleen.
    Exp Hematol. 2011 Mar;39(3):351-359.e3 PMID: 21185906
  20. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology.
    Nature. 2010 Apr 29;464(7293):1371-5 PMID: 20393462
  21. Induction of an IL7-R(+)c-Kit(hi) myelolymphoid progenitor critically dependent on IFN-gamma signaling during acute malaria.
    Nat Immunol. 2010 Jun;11(6):477-85 PMID: 20431620
  22. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis.
    J Exp Med. 2006 Oct 30;203(11):2485-94 PMID: 17030948
  23. Nitric oxide and TNF-alpha trigger colonic inflammation and carcinogenesis in Helicobacter hepaticus-infected, Rag2-deficient mice.
    Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1027-32 PMID: 19164562
  24. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis.
    J Clin Invest. 2008 Jun;118(6):2269-80 PMID: 18497880
  25. Expression of lymphocyte-endothelial receptor-ligand pairs, alpha4beta7/MAdCAM-1 and OX40/OX40 ligand in the colon and jejunum of patients with inflammatory bowel disease.
    Gut. 1999 Dec;45(6):856-63 PMID: 10562584
  26. IL-1R type I-dependent hemopoietic stem cell proliferation is necessary for inflammatory granulopoiesis and reactive neutrophilia.
    J Immunol. 2009 May 15;182(10):6477-84 PMID: 19414802
  27. The transcription factors STAT5A/B regulate GM-CSF-mediated granulopoiesis.
    Blood. 2009 Nov 19;114(21):4721-8 PMID: 19779039
  28. IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses.
    Nature. 2010 Apr 29;464(7293):1362-6 PMID: 20200520
  29. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell.
    Science. 1996 Jul 12;273(5272):242-5 PMID: 8662508
  30. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues.
    Cell. 2007 Nov 30;131(5):994-1008 PMID: 18045540
  31. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages.
    Nature. 2000 Mar 9;404(6774):193-7 PMID: 10724173
  32. Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment.
    Immunity. 2006 Jun;24(6):801-812 PMID: 16782035
  33. Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates.
    J Exp Med. 2005 Dec 5;202(11):1599-611 PMID: 16330818
  34. Requirement of endogenous stem cell factor and granulocyte-colony-stimulating factor for IL-17-mediated granulopoiesis.
    J Immunol. 2000 May 1;164(9):4783-9 PMID: 10779785
  35. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis.
    Immunity. 2008 Apr;28(4):559-70 PMID: 18400195
  36. Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection.
    Nature. 2010 Jun 10;465(7299):793-7 PMID: 20535209
  37. CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms.
    J Exp Med. 2003 Jan 6;197(1):111-9 PMID: 12515818
  38. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis.
    J Immunol. 2006 Nov 1;177(9):5852-60 PMID: 17056509
  39. Monitoring disease activity by stool analyses: from occult blood to molecular markers of intestinal inflammation and damage.
    Gut. 2009 Jun;58(6):859-68 PMID: 19136508
  40. Cyclophosphamide/granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization.
    Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1908-13 PMID: 9050878
  41. Colony-stimulating factors in inflammation and autoimmunity.
    Nat Rev Immunol. 2008 Jul;8(7):533-44 PMID: 18551128
  42. Identification of splenic reservoir monocytes and their deployment to inflammatory sites.
    Science. 2009 Jul 31;325(5940):612-6 PMID: 19644120
Article Info
Journal
Immunity
Abbr.
Immunity
ISSN
1097-4180
DOI
10.1016/j.immuni.2012.08.025
Published
2012-12-14
Epub
2012-00-29
Pages
1116-29
Language
English
Region
United States
NLM ID
9432918
PMCID
PMC3664922
Subset
IM
Grants
Wellcome Trust · 095688 · United Kingdom
Corrections
CommentIn
PMID: 23237962
CommentIn
PMID: 23244717
External Links
PubMed source DOI: 10.1016/j.immuni.2012.08.025 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2