Department of Evolutionary Immunology, Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan.
Department of Immunology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
Front Immunol. 2024 Sep 23;15:1435236. doi: 10.3389/fimmu.2024.1435236. eCollection 2024.
The leukocyte immunoglobulin-like receptor (LILR) family, a group of primate-specific immunoreceptors, is widely expressed on most immune cells and regulates immune responses through interactions with various ligands. The inhibitory type, LILRB, has been extensively studied, and many ligands, such as HLA class I, have been identified. However, the activating type, LILRA, is less understood. We have previously identified microbially cleaved immunoglobulin as a non-self-ligand for LILRA2. In this study, we identified fibrinogen as an endogenous ligand for LILRA2 using mass spectrometry. Although human plasma contains fibrinogen in abundance in its soluble form, LILRA2 only recognizes solid-phase fibrinogen. In addition to the activating LILRA2, fibrinogen was also recognized by the inhibitory LILRB2 and by soluble LILRA3. In contrast, fibrin was recognized by LILRB2 and LILRA3, but not by LILRA2. Moreover, LILRA3 bound more strongly to fibrin than to fibrinogen and blocked the LILRB2-fibrinogen/fibrin interaction. These results suggest that morphological changes in fibrinogen determine whether activating or inhibitory immune responses are induced. Upon recognizing solid-phase fibrinogen, LILRA2 activated human primary monocytes and promoted the expression of various inflammation-related genes, such as chemokines, as revealed by RNA-seq analysis. A blocking antibody against LILRA2 inhibited the fibrinogen-induced inflammatory responses, indicating that LILRA2 is the primary receptor of fibrinogen. Taken together, our findings suggest that solid-phase fibrinogen is an inflammation-inducing endogenous ligand for LILRA2, and this interaction may represent a novel therapeutic target for inflammatory diseases.
白细胞免疫球蛋白样受体 (LILR) 家族是一组灵长类特异性免疫受体，广泛表达于大多数免疫细胞上，并通过与各种配体相互作用来调节免疫反应。抑制型 LILRB 已得到广泛研究，并且已经鉴定出许多配体，如 HLA Ⅰ类。然而，激活型 LILRA 则知之甚少。我们之前已经鉴定出微生物切割的免疫球蛋白是 LILRA2 的非自身配体。在这项研究中，我们使用质谱法鉴定出纤维蛋白原为 LILRA2 的内源性配体。尽管人类血浆中可溶性纤维蛋白原含量丰富，但 LILRA2 仅识别固相纤维蛋白原。除了激活型 LILRA2 外，纤维蛋白原也被抑制型 LILRB2 和可溶性 LILRA3 识别。相比之下，纤维蛋白原被 LILRB2 和 LILRA3 识别，但不被 LILRA2 识别。此外，LILRA3 与纤维蛋白的结合力强于纤维蛋白原，并能阻断 LILRB2-纤维蛋白原/纤维蛋白的相互作用。这些结果表明纤维蛋白原的形态变化决定了是诱导激活型还是抑制型免疫反应。LILRA2 识别固相纤维蛋白原后，激活人原代单核细胞，并通过 RNA-seq 分析促进各种炎症相关基因的表达，如趋化因子。针对 LILRA2 的阻断抗体抑制了纤维蛋白原诱导的炎症反应，表明 LILRA2 是纤维蛋白原的主要受体。综上所述，我们的研究结果表明固相纤维蛋白原是 LILRA2 的炎症诱导内源性配体，这种相互作用可能成为炎症性疾病的新治疗靶点。
