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

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.

• Authors: Jiang-Hu Piao, Hideo Yagita, Ko Okumura, Hiroyasu Nakano
• Journal: Immunology and cell biology (Immunol Cell Biol) Vol. 90 Issue 9 Pg. 881-8 (Oct 2012) ISSN: 1440-1711 [Electronic] United States
• PMID: 22546736 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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