Abnormally differentiated subsets of intestinal macrophage play a key role in Th1-dominant chronic colitis through excess production of IL-12 and IL-23 in response to bacteria
Abnormally differentiated subsets of intestinal macrophage play a key role in Th1-dominant chronic colitis through excess production of IL-12 and IL-23 in response to bacteria
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DOI：
10.4049/jimmunol.175.10.6900
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发表时间：
2005-11-15
影响因子：
4.4
通讯作者：
Hibi, T
中科院分区：
文献类型：
--
作者：
Kamada, N;Hisamatsu, T;Hibi, T
肠道巨噬细胞（mphi）识别肠道细菌的障碍与慢性结肠炎的发病密切相关；然而，确切的机制尚不清楚。本研究的目的是通过使用IL-10缺陷（IL-10(-/-)）小鼠结肠炎模型来阐明M phi在肠道炎症中的作用。gm - csf诱导的骨髓源性M- phi （GM-M - phi）和M- csf诱导的骨髓源性M- phi （M-M - phi）均来源于骨髓CD11b（+）细胞。来自IL-10（-/-）小鼠的M-M phi在热杀全菌Ags刺激下产生异常大量的IL-12和IL-23，而来自野生型（WT）小鼠的M-M phi产生大量的IL-10，但不产生IL-12或IL-23。相比之下，GM-M - phi产生的IL-12在WT和IL-10（-/-）小鼠之间没有显著差异。在离体实验中，WT小鼠结肠固有层M- phi （CLPM phi）而脾脏M- phi的细胞因子产生能力与M-M - phi相似，IL-10（-/-）小鼠的CLPM phi而脾脏M- phi在细菌刺激下也表现出异常的IL-12p70分泌。令人惊讶的是，在分化过程中，IL-10（-/-）小鼠的M-M phi异常IL-12p70分泌量通过补充IL-10得到改善。上述结果提示CLPM phi和M-M phi具有抗炎作用，可抑制WT小鼠细菌诱导的过度炎症。然而，在IL-10（-/-）小鼠中，这种M - phi亚群在IL-10缺乏的环境下分化为异常表型，肠道M - phi异常分化亚群对细菌的识别可能通过IL-12和IL-23的过量产生导致th1显性结肠炎。我们的数据为IL-10（-/-）小鼠结肠炎发生过程中肠道菌群与肠道菌群的关系提供了新的见解。
Disorders in enteric bacteria recognition by intestinal macrophages (M phi) are strongly correlated with the pathogenesis of chronic colitis; however the precise mechanisms remain unclear. The aim of the current study was to elucidate the roles of M phi in intestinal inflammation by using an IL-10-deficient (IL-10(-/-)) mouse colitis model. GM-CSF-induced bone marrow-derived M phi (GM-M phi) and M-CSF-induced bone marrow-derived M phi (M-M phi) were generated from bone marrow CD11b(+) cells. M-M phi from IL-10(-/-) mice produced abnormally large amounts of IL-12 and IL-23 upon stimulation with heat-killed whole bacteria Ags, whereas M-M phi from wild-type (WT) mice produced large amounts of IL-10 but not IL-12 or IL-23. In contrast, IL-12 production by GM-M phi was not significantly different between WT and IL-10(-/-) mice. In ex vivo experiments, cytokine production ability of colonic lamina propria M phi (CLPM phi) but not splenic M phi from WT mice was similar to that of M-M phi, and CLPM phi but not splenic M phi from IL-10(-/-) mice also showed abnormal IL-12p70 hyperproduction upon stimulation with bacteria. Surprisingly, the abnormal IL-12p70 hyperproduction from M-M phi from IL-10(-/-) mice was improved by IL-10 supplementation during the differentiation process. These results suggest that CLPM phi and M-M phi act as anti-inflammatory M phi and suppress excess inflammation induced by bacteria in WT mice. In IL-10(-/-) mice, however, such M phi subsets differentiated into an abnormal phenotype under an IL-10-deficient environment, and bacteria recognition by abnormally differentiated subsets of intestinal M phi may lead to Th1-dominant colitis via IL-12 and IL-23 hyperproduction. Our data provide new insights into the intestinal M phi to gut flora relationship in the development of colitis in IL-10(-/-) mice.