Izawa Kumi, Kitaura Jiro, Yamanishi Yoshinori, Matsuoka Takayuki, Oki Toshihiko, Shibata Fumi, Kumagai Hidetoshi, Nakajima Hideaki, Maeda-Yamamoto Mari, Hauchins Jeffrey P, Tybulewicz Victor L J, Takai Toshiyuki, Kitamura Toshio
Division of Cellular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
National Institute of Vegetable and Tea Science, National Agriculture Research Organization, 2769 Kanaya, Shizuoka 428-8501, Japan.
J Biol Chem. 2007 Jun 22;282(25):17997-18008. doi: 10.1074/jbc.M701100200. Epub 2007 Apr 16.
The leukocyte mono-Ig-like receptor (LMIR) belongs to a new family of paired immunoreceptors. In this study, we analyzed activating receptor LMIR4/CLM-5 as a counterpart of inhibitory receptor LMIR3/CLM-1. LMIR4 is expressed in myeloid cells, including granulocytes, macrophages, and mast cells, whereas LMIR3 is more broadly expressed. The association of LMIR4 with Fc receptor-gamma among immunoreceptor tyrosine-based activation motif-bearing molecules was indispensable for LMIR4-mediated functions of bone marrow-derived mast cells, but dispensable for its surface expression. Cross-linking of LMIR4 led to Lyn- and Syk-dependent activation of bone marrow-derived mast cells, resulting in cytokine production and degranulation, whereas that of LMIR3 did not. The triggering of LMIR4 and TLR4 synergistically caused robust cytokine production in accordance with enhanced activation of ERK, whereas the co-ligation of LMIR4 and LMIR3 dramatically abrogated cytokine production. Notably, intraperitoneal administration of lipopolysaccharide strikingly up-regulated LMIR3 and down-regulated LMIR4, whereas that of granulocyte colony-stimulating factor up-regulated both LMIR3 and LMIR4 in granulocytes. Cross-linking of LMIR4 in bone marrow granulocytes also resulted in their activation, which was enhanced by lipopolysaccharide. Collectively, these results suggest that the innate immune system is at least in part regulated by the qualitative and quantitative balance of the paired receptors LMIR3 and LMIR4.
白细胞单免疫球蛋白样受体（LMIR）属于一类新的配对免疫受体家族。在本研究中，我们分析了激活型受体LMIR4/CLM-5作为抑制型受体LMIR3/CLM-1的对应物。LMIR4在髓样细胞中表达，包括粒细胞、巨噬细胞和肥大细胞，而LMIR3的表达更为广泛。在基于免疫受体酪氨酸的激活基序的分子中，LMIR4与Fc受体γ的结合对于骨髓来源肥大细胞的LMIR4介导的功能是不可或缺的，但对于其表面表达是可有可无的。LMIR4的交联导致骨髓来源肥大细胞的Lyn和Syk依赖性激活，从而导致细胞因子产生和脱颗粒，而LMIR3的交联则不会。LMIR4和TLR4的触发协同导致强大的细胞因子产生，这与ERK的激活增强一致，而LMIR4和LMIR3的共同连接则显著消除细胞因子产生。值得注意的是，腹腔注射脂多糖显著上调LMIR3并下调LMIR4，而粒细胞集落刺激因子的腹腔注射则上调粒细胞中的LMIR3和LMIR4。骨髓粒细胞中LMIR4的交联也导致它们的激活，脂多糖可增强这种激活。总的来说，这些结果表明先天免疫系统至少部分受配对受体LMIR3和LMIR4的定性和定量平衡调节。
