Department of Pediatrics, University of Tennessee Health Science Center, 50 N. Dunlap, Rm. 461R, Memphis, TN 38103, USA.
Department of Medicine, University of Tennessee Health Science Center, 956 Court Ave., Memphis, TN 38163, USA.
Int J Mol Sci. 2022 Aug 30;23(17):9833. doi: 10.3390/ijms23179833.
Citrullination of proteins plays an important role in protein function and it has recently become clear that citrullinated proteins play a role in immune responses. In this study we examined how citrullinated collagen, an extracellular matrix protein, affects T-cell function during the development of autoimmune arthritis. Using an HLA-DR1 transgenic mouse model of rheumatoid arthritis, mice were treated intraperitoneally with either native type I collagen (CI), citrullinated CI (cit-CI), or phosphate buffered saline (PBS) prior to induction of autoimmune arthritis. While the mice given native CI had significantly less severe arthritis than controls administered PBS, mice receiving cit-CI had no decrease in the severity of autoimmune arthritis. Using Jurkat cells expressing the inhibitory receptor leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1), Western blot analysis indicated that while CI and cit-CI bound to LAIR-1 with similar affinity, only CI induced phosphorylation of the LAIR ITIM tyrosines; cit-CI was ineffective. These data suggest that cit-CI acts as an antagonist of LAIR-1 signaling, and that the severity of autoimmune arthritis can effectively be altered by targeting T cells with citrullinated collagen.
蛋白质的瓜氨酸化在蛋白质功能中起着重要作用，最近人们清楚地认识到，瓜氨酸化蛋白在免疫反应中发挥作用。在这项研究中，我们研究了细胞外基质蛋白瓜氨酸化胶原蛋白如何影响自身免疫性关节炎发展过程中的 T 细胞功能。使用 HLA-DR1 转基因类风湿关节炎小鼠模型，在诱导自身免疫性关节炎之前，通过腹腔内给予天然 I 型胶原蛋白 (CI)、瓜氨酸化 CI (cit-CI) 或磷酸盐缓冲盐水 (PBS) 对小鼠进行处理。尽管给予天然 CI 的小鼠的关节炎严重程度明显低于给予 PBS 的对照组，但给予 cit-CI 的小鼠的自身免疫性关节炎严重程度没有降低。使用表达抑制性受体白细胞相关免疫球蛋白样受体-1 (LAIR-1) 的 Jurkat 细胞进行 Western blot 分析表明，虽然 CI 和 cit-CI 与 LAIR-1 的结合亲和力相似，但只有 CI 诱导 LAIR ITIM 酪氨酸的磷酸化；cit-CI 无效。这些数据表明 cit-CI 作为 LAIR-1 信号的拮抗剂起作用，并且通过用瓜氨酸化胶原蛋白靶向 T 细胞可以有效改变自身免疫性关节炎的严重程度。
