Identification of FcαRI as an inhibitory receptor that controls inflammation:: Dual role of FcRγ ITAM
Identification of FcαRI as an inhibitory receptor that controls inflammation:: Dual role of FcRγ ITAM
复制标题
DOI：
10.1016/j.immuni.2004.11.017
复制
发表时间：
2005-01-01
期刊：
影响因子：
32.4
通讯作者：
Monteiro, RC
中科院分区：
文献类型：
--
作者：
Pasquier, B;Launay, P;Monteiro, RC
血清伊加被认为是具有多种抗炎功能的免疫系统的离散管家，而IgA-免疫复合物介导炎症反应。在这里，我们确定FcalphaRI作为决定伊加反应的性质的分子装置。在不存在持续聚集的情况下，通过血清伊加或抗-FalphaRI Fab的受体靶向抑制异源Fc γ R或Fc ε RI的活化应答。其抑制机制涉及酪氨酸磷酸酶SHP-1向FcalphaRI的募集以及FcepsilonRI结合诱导的Syk、LAT和ERK磷酸化的损伤。SHP-1的募集依赖于ERK。相反，FcalphaRI通过多聚体配体的持续聚集通过募集大量Syk和中止SHP-1结合来刺激细胞活化。两种类型的信号都需要FcR γ-ITAM基序。抗FcalphaRI Fab治疗抑制FcalphaRI转基因小鼠中过敏性哮喘的表现。这些发现将FcalphaRI重新定义为免疫系统的双功能抑制/激活受体，其介导伊加的抗炎和促炎功能。
Serum IgA is considered a discrete housekeeper of the immune system with multiple anti-inflammatory functions, whereas IgA-immune complexes mediate inflammatory responses. Here, we identify FcalphaRI as a molecular device that determines the nature of IgA responses. In the absence of sustained aggregation, receptor targeting by serum IgA or anti-FalphaRI Fab inhibits activating responses of heterologous FcgammaR or FcepsilonRI. The inhibitory mechanism involves recruitment of tyrosine phosphatase SHP-1 to FcalphaRI and impairment of Syk, LAT, and ERK phosphorylation induced by FcepsilonRI engagement. SHP-1 recruitment is dependent on ERK. Conversely, sustained aggregation of FcalphaRI by multimeric ligands stimulates cell activation by recruiting high amounts of Syk and aborting SHP-1 binding. Both types of signals require the FcRgamma-ITAM motif. Anti-FcalphaRI Fab treatment suppresses manifestations of allergic asthma in FcalphaRI transgenic mice. These findings redefine FcalphaRI as a bifunctional inhibitory/activating receptor of the immune system that mediates both anti- and proinflammatory functions of IgA.