Aberrant accumulation of interleukin-10-secreting neutrophils in TRAF2-deficient mice

Immunol Cell Biol. 2012 Oct;90(9):881-8. doi: 10.1038/icb.2012.22. Epub 2012 May 1.

Abstract

Highly coordinated expression of inflammatory and anti-inflammatory cytokines is crucial for maintaining homeostasis of the gut that is constantly exposed to large amounts of commensal bacteria. We have previously reported that tumor necrosis factor (TNF) receptor-associated factor (Traf)2(-/-) mice spontaneously develop severe colitis and that the development of colitis largely depends on TNFα-dependent apoptosis of colonic epithelial cells. However, the detailed molecular mechanisms underlying the immunological disorders of Traf2(-/-) mice are not fully understood. Here we show that interleukin (IL)-10-secreting neutrophils accumulated in peripheral blood and bone marrow (BM) cells from Traf2(-/-) mice compared with those from wild-type mice. Treatment of Traf2(-/-) mice with neutralizing antibody against TNFα or crossing Traf2(-/-) mice with Tnfr1(-/-) mice reduced the percentages of IL-10-secreting neutrophils, suggesting that the development of IL-10-secreting neutrophils largely depended on TNFα signals. Moreover, stimulation of BM cells from wild-type mice with lipopolysaccharide and Pam3CS(K)4, a ligand for Toll-like receptor 4 and 2, respectively, induced differentiation of BM cells into IL-10-secreting neutrophils. These results suggest that the development of IL-10-secreting neutrophils is not restricted to Traf2(-/-) mice, but could be generalized to wild-type mice under certain conditions such as inflammation. Finally, combined treatment of Traf2(-/-) mice with neutralizing antibodies against TNFα and IL-10, but not each antibody alone, substantially ameliorated colitis and prolonged survival. Together, abrogation of immunosuppressive conditions mediated by IL-10-secreting neutrophils might be an alternative strategy to treat chronic inflammatory diseases at least under certain conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / pharmacology
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / metabolism
  • Bone Marrow Transplantation
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology
  • Colitis / immunology
  • Colitis / metabolism
  • Colitis / prevention & control
  • Female
  • Flow Cytometry
  • Interleukin-10 / genetics
  • Interleukin-10 / immunology*
  • Interleukin-10 / metabolism
  • Lipopeptides / pharmacology
  • Lipopolysaccharides / pharmacology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Neutrophils / immunology*
  • Neutrophils / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / deficiency
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / immunology*
  • Survival Analysis
  • TNF Receptor-Associated Factor 2 / deficiency
  • TNF Receptor-Associated Factor 2 / genetics
  • TNF Receptor-Associated Factor 2 / immunology*
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antibodies, Neutralizing
  • Lipopeptides
  • Lipopolysaccharides
  • Pam2CSK4 lipopeptide
  • Receptors, Tumor Necrosis Factor, Type I
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha
  • Interleukin-10