Alternatively activated macrophage-derived RELM-{alpha} is a negative regulator of type 2 inflammation in the lung.
Alternatively activated macrophage-derived RELM-{alpha} is a negative regulator of type 2 inflammation in the lung.
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DOI：
10.1084/jem.20082048
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发表时间：
2009-04-13
期刊：
影响因子：
--
通讯作者：
Artis D
中科院分区：
文献类型：
--
作者：
Nair MG;Du Y;Perrigoue JG;Zaph C;Taylor JJ;Goldschmidt M;Swain GP;Yancopoulos GD;Valenzuela DM;Murphy A;Karow M;Stevens S;Pearce EJ;Artis D
选择性激活的巨噬细胞（AAMacs）的分化和募集是与感染、过敏、糖尿病和癌症相关的几种炎症性疾病的标志。AAMacs由精氨酸酶1、几丁质酶样分子和抵抗素样分子（RELM）α/FIZZ 1的表达定义;然而，这些分子对炎症性疾病的发生、进展或消退的影响尚不清楚。我们描述了RELM-α缺陷（Retnla−/−）小鼠的产生，并使用辅助性T细胞2型（Th 2）白细胞介素依赖性肺部炎症模型来确定RELM-α的免疫调节作用。在用曼氏血吸虫（Sm）卵攻击后，Retnla−/−小鼠与野生型小鼠相比发生了加重的肺部炎症，其特征是过度的肺血管化，卵诱导的肉芽肿大小增加和纤维化增加。与疾病严重程度增加相关的是，Sm卵攻击的Retnla−/−小鼠表现出病原体特异性CD 4 + T细胞衍生的Th 2细胞因子的表达升高。与免疫调节特性一致，重组RELM-α可以与巨噬细胞和效应性CD 4 + Th 2细胞结合，并以布鲁顿酪氨酸激酶依赖的方式抑制Th 2细胞因子的产生。此外，Retnla−/− AAMacs促进了过度的抗原特异性Th 2细胞分化。总的来说，这些数据确定了AAMac衍生的RELM-α在限制Th 2细胞介导的肺部炎症发病机制中的先前未被认识的作用，部分通过调节CD 4 + T细胞应答。
Differentiation and recruitment of alternatively activated macrophages (AAMacs) are hallmarks of several inflammatory conditions associated with infection, allergy, diabetes, and cancer. AAMacs are defined by the expression of Arginase 1, chitinase-like molecules, and resistin-like molecule (RELM) α/FIZZ1; however, the influence of these molecules on the development, progression, or resolution of inflammatory diseases is unknown. We describe the generation of RELM-α–deficient (Retnla−/−) mice and use a model of T helper type 2 (Th2) cytokine-dependent lung inflammation to identify an immunoregulatory role for RELM-α. After challenge with Schistosoma mansoni (Sm) eggs, Retnla−/− mice developed exacerbated lung inflammation compared with their wild-type counterparts, characterized by excessive pulmonary vascularization, increased size of egg-induced granulomas, and elevated fibrosis. Associated with increased disease severity, Sm egg–challenged Retnla−/− mice exhibited elevated expression of pathogen-specific CD4+ T cell–derived Th2 cytokines. Consistent with immunoregulatory properties, recombinant RELM-α could bind to macrophages and effector CD4+ Th2 cells and inhibited Th2 cytokine production in a Bruton's tyrosine kinase–dependent manner. Additionally, Retnla−/− AAMacs promoted exaggerated antigen-specific Th2 cell differentiation. Collectively, these data identify a previously unrecognized role for AAMac-derived RELM-α in limiting the pathogenesis of Th2 cytokine-mediated pulmonary inflammation, in part through the regulation of CD4+ T cell responses.
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