An Activating and Inhibitory Signal from an Inhibitory Receptor LMIR3/CLM-1: LMIR3 Augments Lipopolysaccharide Response through Association with FcRγ in Mast Cells
An Activating and Inhibitory Signal from an Inhibitory Receptor LMIR3/CLM-1: LMIR3 Augments Lipopolysaccharide Response through Association with FcRγ in Mast Cells
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DOI：
10.4049/jimmunol.0900552
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发表时间：
2009-07-15
影响因子：
4.4
通讯作者：
Kitamura, Toshio
中科院分区：
文献类型：
--
作者：
Izawa, Kumi;Kitaura, Jiro;Kitamura, Toshio
白细胞单免疫球蛋白样受体3（LMIR 3）是一种主要在骨髓细胞中表达的抑制性受体。Fc ε RI和LMIR 3的共同参与损害了由Fc ε RI单独交联诱导的骨髓源性肥大细胞（BMMC）中细胞因子的产生。小鼠LMIR 3具有5个胞质酪氨酸残基（Y241、Y276、Y289、Y303、Y325），其中Y241和Y289（Y241/289）或Y325分别符合ITIM或基于免疫酪氨酸的开关基序（ITSM）的共有序列。根据Y241/289/325协同募集含Src同源区2结构域的磷酸酶1（SHP）-1或SHP-2的潜力，通过用苯丙氨酸（Y241/189/325/F）替代Y241/289以及Y325来消除抑制作用。有趣的是，LMIR 3交联单独诱导表达LMIR 3（Y241/276/289/303/325 F）突变体以及LMIR 3（Y241/289/325 F）的BMMC中的细胞因子产生。此外，免疫共沉淀实验显示，LMIR 3与含ITAM的FcR γ相关。对FeR γ缺陷BMMC的分析表明，Y276/303和FcR γ在该抑制性受体的激活功能中起关键作用。重要的是，LMIR 3交联增强了LPS刺激的BMMC的细胞因子产生，同时抑制了其他TLR激动剂或干细胞因子刺激的产生。因此，抑制性受体LMIR 3具有与FcR γ结合的独特性质，从而与TLR 4刺激一起作为活化性受体发挥作用。免疫学杂志，2009，183：925-936.
Leukocyte mono-Ig-like receptor 3 (LMIR3) is an inhibitory receptor mainly expressed in myeloid cells. Coengagement of Fc epsilon RI and LMIR3 impaired cytokine production in bone marrow-derived mast cells (BMMCs) induced by Fc epsilon RI crosslinking alone. Mouse LMIR3 possesses five cytoplasmic tyrosine residues (Y241, Y276, Y289, Y303, Y325), among which Y241 and Y289 (Y241/289) or Y325 fit the consensus sequence of ITIM or immunotyrosine-based switch motif (ITSM), respectively. The inhibitory effect was abolished by the replacement of Y325 in addition to Y241/289 with phenylalanine (Y241/189/325/F) in accordance with the potential of Y241/289/325 to cooperatively recruit Src homology region 2 domain-containing phosphatase 1 (SHP)-1 or SHP-2. Intriguingly, LMIR3 crosslinking alone induced cytokine production in BMMCs expressing LMIR3 (Y241/276/289/303/325F) mutant as well as LMIR3 (Y241/289/325F). Moreover, coimmunoprecipitation experiments revealed that LMIR3 associated with ITAM-containing FcR gamma. Analysis of FeR gamma-deficient BMMCs demonstrated that both Y276/303 and FcR gamma played a critical role in the activating function of this inhibitory receptor. Importantly, LMIR3 crosslinking enhanced cytokine production of BMMCs stimulated by LPS, while suppressing production stimulated by other TLR agonists or stem cell factor. Thus, an inhibitory receptor LMIR3 has a unique property to associate with FcR gamma and thereby functions as an activating receptor in concert with TLR4 stimulation. The Journal of Immunology, 2009, 183: 925-936.