Aberrant accumulation of interleukin-10-secreting neutrophils in TRAF2-deficient mice.
Aberrant accumulation of interleukin-10-secreting neutrophils in TRAF2-deficient mice.
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TRAF2 缺陷小鼠中分泌白细胞介素 10 的中性粒细胞异常积累。
DOI：
10.1038/icb.2012.22
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发表时间：
2012
影响因子：
4
通讯作者：
Piao JH
中科院分区：
文献类型：
--
作者：
Yoshikawa;S.;Oh-hora;M.;Miyake;K.;Li;L.;Ohta;T.;Adachi;T.;Horiguchi;K.;Kawano;Y.;Karasuyama;H.;Piao JH
炎症和抗炎细胞因子的高度协调表达对于维持持续暴露于大量肠道细菌的肠道的稳态至关重要。我们以前曾报道过肿瘤坏死因子（TNF）受体相关因子（Traf）2−/−小鼠自发发生重度结肠炎，结肠炎的发生在很大程度上取决于结肠上皮细胞的TNFα依赖性凋亡。然而，Traf 2 −/−小鼠免疫紊乱的详细分子机制尚未完全了解。在这里，我们发现分泌白细胞介素（IL）-10-的中性粒细胞在Traf 2 −/−小鼠的外周血和骨髓（BM）细胞中积累，与野生型小鼠相比。用TNFα中和抗体处理Traf 2 −/−小鼠或将Traf 2 −/−小鼠与Tnfr 1 −/−小鼠杂交，可降低分泌IL-10的中性粒细胞的百分比，这表明分泌IL-10的中性粒细胞的发育在很大程度上取决于TNFα信号。此外，分别用脂多糖和Toll样受体4和2的配体Pam 3CS（K）4刺激野生型小鼠的BM细胞，诱导BM细胞分化为分泌IL-10的中性粒细胞。这些结果表明，分泌IL-10的中性粒细胞的发育并不局限于Traf 2 −/−小鼠，但在某些条件下，如炎症，可以推广到野生型小鼠。最后，联合使用TNFα和IL-10的中和抗体治疗Traf 2 −/−小鼠，而不是单独使用每种抗体，大大改善了结肠炎并延长了生存期。总之，消除由IL-10分泌中性粒细胞介导的免疫抑制条件可能是至少在某些条件下治疗慢性炎症性疾病的替代策略。
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 ofTraf2−/−mice are not fully understood. Here we show that interleukin (IL)‐10‐secreting neutrophils accumulated in peripheral blood and bone marrow (BM) cells fromTraf2−/−mice compared with those from wild‐type mice. Treatment ofTraf2−/−mice with neutralizing antibody against TNFα or crossingTraf2−/−mice withTnfr1−/−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 toTraf2−/−mice, but could be generalized to wild‐type mice under certain conditions such as inflammation. Finally, combined treatment ofTraf2−/−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.