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Molecular Medicine

, Volume 20, Issue 1, pp 707–719 | Cite as

Expression of Blimp-1 in Dendritic Cells Modulates the Innate Inflammatory Response in Dextran Sodium Sulfate-Induced Colitis

  • Sun Jung Kim
  • Jordan Goldstein
  • Kimberly Dorso
  • Miriam Merad
  • Lloyd Mayer
  • James M. Crawford
  • Peter K. Gregersen
  • Betty Diamond
Research Article

Abstract

A single nucleotide polymorphism of PRDM1, the gene encoding Blimp-1, is strongly associated with inflammatory bowel disease. Here, we demonstrate that Blimp-1 in CD103+ dendritic cells (DCs) critically contributes to the regulation of macrophage homeostasis in the colon. Dextran sodium sulfate (DSS)-exposed Blimp-1cko mice with a deletion of Blimp-1 in CD103+ DCs and CD11chi macrophages exhibited severe inflammatory symptoms, pronounced weight loss, high mortality, robust infiltration of neutrophils in epithelial regions of the colon, an increased expression of proinflammatory cytokines and a significant decrease in CD103+ DCs in the colon compared with DSS exposed wild-type (WT) mice. Purified colonic macrophages from Blimp-1cko mice expressed increased levels of matrix metalloproteinase 8, 9 and 12 mRNA. WT macrophages cocultured with colonic DCs but not bone marrow-derived DCs from Blimp-1cko produced increased matrix metalloproteinases in an interleukin (IL)-1β- and IL-6-dependent manner. Treatment of Blimp-1cko mice with anti-IL-1β and anti-IL-6 abrogated the exaggerated clinical response. Overall, these data demonstrate that Blimp-1 expression in DCs can alter an innate inflammatory response by modulating the activation of myeloid cells. This is a novel mechanism of contribution of Blimp-1 for the pathogenesis of inflammatory bowel diseases, implicating another therapeutic target for the development of inflammatory bowel disease.

Notes

Acknowledgments

We thank M Bogunovic for teaching the intestinal myeloid cell isolation technique and G Honig for helping with the assessment of systemic bacteremia. We thank H Borrero and C Colon at the Flow Cytometry core facility.

Supplementary material

10020_2014_2001707_MOESM1_ESM.pdf (380 kb)
Supplementary material, approximately 379 KB.

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© The Author(s) 2014

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Authors and Affiliations

  • Sun Jung Kim
    • 1
    • 2
  • Jordan Goldstein
    • 1
  • Kimberly Dorso
    • 1
  • Miriam Merad
    • 3
  • Lloyd Mayer
    • 4
  • James M. Crawford
    • 5
  • Peter K. Gregersen
    • 2
    • 6
  • Betty Diamond
    • 1
    • 2
    • 7
  1. 1.The Center for Autoimmune and Musculoskeletal DiseasesThe Feinstein Institute for Medical ResearchManhassetUSA
  2. 2.Department of Molecular Medicine, School of MedicineHofstra UniversityHempsteadUSA
  3. 3.The Human Immunology CenterIcahn School of Medicine at Mount SinaiNew YorkUSA
  4. 4.The Immunology InstituteIcahn School of Medicine at Mount SinaiNew YorkUSA
  5. 5.Department of Pathology and Laboratory MedicineHofstra North Shore-LIJ School of MedicineHempsteadUSA
  6. 6.Center for Genomics and Human GeneticsThe Feinstein Institute for Medical ResearchManhassetUSA
  7. 7.ManhassetUSA

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