Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis.
Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis.
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DOI：
10.1371/journal.ppat.1000371
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发表时间：
2009-04
期刊：
影响因子：
6.7
通讯作者：
Wynn TA
中科院分区：
文献类型：
--
作者：
Pesce JT;Ramalingam TR;Mentink-Kane MM;Wilson MS;El Kasmi KC;Smith AM;Thompson RW;Cheever AW;Murray PJ;Wynn TA
精氨酸酶-1的巨噬细胞特异性表达通常被认为通过增强L-脯氨酸、多胺和Th 2细胞因子的产生来促进炎症、纤维化和伤口愈合。然而，在这里，我们表明，巨噬细胞特异性Arg 1的功能作为炎症和纤维化的抑制剂感染后的Th 2诱导病原体曼氏血吸虫。尽管巨噬细胞中Arg 1的条件性缺失不影响感染易感性，但Arg 1 −/flox ;LysMcre小鼠的死亡率加快。死亡率不是由于急性Th 1/NOS 2介导的肝毒性或内毒素血症。相反，感染Arg 1 −/flox ;LysMcre小鼠的肉芽肿性炎症、肝纤维化和门静脉高压增加。Arg 1 flox/flox ; Tie 2cre小鼠也获得了类似的发现，这些小鼠在所有巨噬细胞群体中删除了Arg 1。在感染的Arg 1 −/flox ;LysMcre小鼠中，Th 2细胞因子的产生增加，并且与交替激活的野生型巨噬细胞不同，Arg 1 −/flox ;LysMcre巨噬细胞在体外无法抑制T细胞增殖，这为Th 2病理学的恶化提供了潜在机制。Arg 1表达巨噬细胞的抑制活性不依赖于IL-10和TGF-β1。然而，当提供外源性L-精氨酸时，T细胞增殖恢复，表明Arg 1表达巨噬细胞耗尽精氨酸，这是维持CD 4 + T细胞应答所需的。这些数据确定Arg 1作为替代性激活的巨噬细胞（AAM）的基本抑制介质，并表明Arg 1表达的巨噬细胞作为抑制剂，而不是诱导Th 2依赖性炎症和纤维化的功能。虽然NOS 2在Th 1型免疫中的功能已被广泛研究，但Arg 1在调节Th 2型应答中的作用尚不清楚。以前，我们表明，脯氨酸的生产AAMs是由Arg 1活性调节。由于脯氨酸是肌成纤维细胞中胶原合成所必需的，许多研究表明，Arg 1表达AAM调节伤口愈合和纤维化。血吸虫病纤维化的发展依赖于Th 2细胞因子，IL-4/IL-13缺陷的小鼠不能上调Arg 1。然而，尽管Arg 1表达与Th 2依赖性纤维化相关，但巨噬细胞特异性Arg 1对血吸虫病纤维化发病机制的贡献尚不清楚。在这里进行的研究与两种不同的小鼠品系缺乏巨噬细胞相关的Arg 1明确表明，Arg 1表达的巨噬细胞表现出抗炎和抗纤维化活性在Th 2驱动的炎症反应。在血吸虫病中，纤维化、门静脉高压和静脉曲张出血是人类严重肝脾型疾病的主要病理变化。人们普遍认为，当慢性感染链球菌时，不能充分激活免疫抑制机制的人。mansoni是最终发展成严重疾病的个体。我们的数据确定Arg 1表达巨噬细胞作为慢性血吸虫病免疫下调的关键介质。
Macrophage-specific expression of Arginase-1 is commonly believed to promote inflammation, fibrosis, and wound healing by enhancing L-proline, polyamine, and Th2 cytokine production. Here, however, we show that macrophage-specific Arg1 functions as an inhibitor of inflammation and fibrosis following infection with the Th2-inducing pathogen Schistosoma mansoni. Although susceptibility to infection was not affected by the conditional deletion of Arg1 in macrophages, Arg1 −/flox ;LysMcre mice died at an accelerated rate. The mortality was not due to acute Th1/NOS2-mediated hepatotoxicity or endotoxemia. Instead, granulomatous inflammation, liver fibrosis, and portal hypertension increased in infected Arg1 −/flox ;LysMcre mice. Similar findings were obtained with Arg1 flox/flox ;Tie2cre mice, which delete Arg1 in all macrophage populations. Production of Th2 cytokines increased in the infected Arg1 −/flox ;LysMcre mice, and unlike alternatively activated wild-type macrophages, Arg1 −/flox ;LysMcre macrophages failed to inhibit T cell proliferation in vitro, providing an underlying mechanism for the exacerbated Th2 pathology. The suppressive activity of Arg1-expressing macrophages was independent of IL-10 and TGF-β1. However, when exogenous L-arginine was provided, T cell proliferation was restored, suggesting that Arg1-expressing macrophages deplete arginine, which is required to sustain CD4+ T cell responses. These data identify Arg1 as the essential suppressive mediator of alternatively activated macrophages (AAM) and demonstrate that Arg1-expressing macrophages function as suppressors rather than inducers of Th2-dependent inflammation and fibrosis. While the function of NOS2 in Th1-type immunity has been investigated extensively, the role of Arg1 in the regulation of Th2-type responses is unclear. Previously, we showed that proline production in AAMs is regulated by Arg1 activity. Because proline is essential for collagen synthesis in myofibroblasts, numerous studies have suggested that Arg1-expressing AAMs regulate wound healing and fibrosis. The development of fibrosis in schistosomiasis is dependent on Th2 cytokines, and mice deficient in IL-4/IL-13 fail to upregulate Arg1. Nevertheless, although Arg1 expression is associated with Th2-dependent fibrosis, the contribution of macrophage-specific Arg1 to the pathogenesis of fibrosis in schistosomiasis was unknown. The studies conducted here with two different strains of mice deficient in macrophage-associated Arg1 demonstrate unequivocally that Arg1-expressing macrophages exhibit both anti-inflammatory and anti-fibrotic activity during Th2-driven inflammatory responses. In schistosomiasis, fibrosis, portal hypertension, and variceal bleeding are the primary pathological changes that characterize the severe hepatosplenic form of the disease in humans. It is widely believed that people who fail to adequately activate immune suppressive mechanisms when chronically infected with S. mansoni are the individuals who ultimately develop severe disease. Our data identify Arg1-expressing macrophages as critical mediators of immune downmodulation in chronic schistosomiasis.
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