Faridi Mohd Hafeez, Khan Samia Q, Zhao Wenpu, Lee Ha Won, Altintas Mehmet M, Zhang Kun, Kumar Vinay, Armstrong Andrew R, Carmona-Rivera Carmelo, Dorschner Jessica M, Schnaith Abigail M, Li Xiaobo, Ghodke-Puranik Yogita, Moore Erica, Purmalek Monica, Irizarry-Caro Jorge, Zhang Tingting, Day Rachael, Stoub Darren, Hoffmann Victoria, Khaliqdina Shehryar Jehangir, Bhargava Prachal, Santander Ana M, Torroella-Kouri Marta, Issac Biju, Cimbaluk David J, Zloza Andrew, Prabhakar Rajeev, Deep Shashank, Jolly Meenakshi, Koh Kwi Hye, Reichner Jonathan S, Bradshaw Elizabeth M, Chen JianFeng, Moita Luis F, Yuen Peter S, Li Tsai Wanxia, Singh Bhupinder, Reiser Jochen, Nath Swapan K, Niewold Timothy B, Vazquez-Padron Roberto I, Kaplan Mariana J, Gupta Vineet
J Clin Invest. 2017 Apr 3;127(4):1271-1283. doi: 10.1172/JCI88442. Epub 2017 Mar 6.
Genetic variations in the ITGAM gene (encoding CD11b) strongly associate with risk for systemic lupus erythematosus (SLE). Here we have shown that 3 nonsynonymous ITGAM variants that produce defective CD11b associate with elevated levels of type I interferon (IFN-I) in lupus, suggesting a direct link between reduced CD11b activity and the chronically increased inflammatory status in patients. Treatment with the small-molecule CD11b agonist LA1 led to partial integrin activation, reduced IFN-I responses in WT but not CD11b-deficient mice, and protected lupus-prone MRL/Lpr mice from end-organ injury. CD11b activation reduced TLR-dependent proinflammatory signaling in leukocytes and suppressed IFN-I signaling via an AKT/FOXO3/IFN regulatory factor 3/7 pathway. TLR-stimulated macrophages from CD11B SNP carriers showed increased basal expression of IFN regulatory factor 7 (IRF7) and IFN-β, as well as increased nuclear exclusion of FOXO3, which was suppressed by LA1-dependent activation of CD11b. This suggests that pharmacologic activation of CD11b could be a potential mechanism for developing SLE therapeutics.
整合素α-M（ITGAM）基因（编码CD11b）的遗传变异与系统性红斑狼疮（SLE）的发病风险密切相关。我们在此表明，3种产生缺陷型CD11b的非同义ITGAM变异与狼疮患者中I型干扰素（IFN-I）水平升高有关，提示CD11b活性降低与患者慢性炎症状态增加之间存在直接联系。用小分子CD11b激动剂LA1治疗可导致部分整合素激活，降低野生型而非CD11b缺陷型小鼠的IFN-I反应，并保护易患狼疮的MRL/Lpr小鼠免受终末器官损伤。CD11b激活可降低白细胞中TLR依赖性促炎信号，并通过AKT/FOXO3/IFN调节因子3/7途径抑制IFN-I信号。来自CD11B单核苷酸多态性携带者的TLR刺激巨噬细胞显示IFN调节因子7（IRF7）和IFN-β的基础表达增加，以及FOXO3的核排除增加，而LA1依赖性的CD11b激活可抑制这种增加。这表明CD11b的药理激活可能是开发SLE治疗药物的潜在机制。
