Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, New York, USA.
Rutgers Graduate School of Biomedical Sciences, Newark, New Jersey, USA.
J Clin Invest. 2020 Dec 1;130(12):6700-6717. doi: 10.1172/JCI120288.
The transcription factor IFN regulatory factor 5 (IRF5) is a central mediator of innate and adaptive immunity. Genetic variations within IRF5 are associated with a risk of systemic lupus erythematosus (SLE), and mice lacking Irf5 are protected from lupus onset and severity, but how IRF5 functions in the context of SLE disease progression remains unclear. Using the NZB/W F1 model of murine lupus, we show that murine IRF5 becomes hyperactivated before clinical onset. In patients with SLE, IRF5 hyperactivation correlated with dsDNA titers. To test whether IRF5 hyperactivation is a targetable function, we developed inhibitors that are cell permeable, nontoxic, and selectively bind to the inactive IRF5 monomer. Preclinical treatment of NZB/W F1 mice with an inhibitor attenuated lupus pathology by reducing serum antinuclear autoantibodies, dsDNA titers, and the number of circulating plasma cells, which alleviated kidney pathology and improved survival. Clinical treatment of MRL/lpr and pristane-induced lupus mice with an inhibitor led to significant reductions in dsDNA levels and improved survival. In ex vivo human studies, the inhibitor blocked SLE serum-induced IRF5 activation and reversed basal IRF5 hyperactivation in SLE immune cells. We believe this study provides the first in vivo clinical support for treating patients with SLE with an IRF5 inhibitor.
转录因子 IFN 调节因子 5（IRF5）是先天和适应性免疫的重要介质。IRF5 内的遗传变异与系统性红斑狼疮（SLE）的风险相关，缺乏 Irf5 的小鼠可免受狼疮发病和严重程度的影响，但 IRF5 在 SLE 疾病进展中的作用机制尚不清楚。使用 NZB/W F1 狼疮小鼠模型，我们发现小鼠 IRF5 在临床发病前就被过度激活。在 SLE 患者中，IRF5 的过度激活与 dsDNA 滴度相关。为了测试 IRF5 的过度激活是否是一个可靶向的功能，我们开发了细胞通透性、无毒且选择性地与无活性 IRF5 单体结合的抑制剂。抑制剂对 NZB/W F1 小鼠的临床前治疗通过降低血清抗核自身抗体、dsDNA 滴度和循环浆细胞的数量来减轻狼疮病理，从而缓解肾脏病理并提高生存率。抑制剂对 MRL/lpr 和 pristane 诱导的狼疮小鼠的临床治疗导致 dsDNA 水平显著降低，生存率提高。在体外人类研究中，抑制剂阻断了 SLE 血清诱导的 IRF5 激活，并逆转了 SLE 免疫细胞中的基础 IRF5 过度激活。我们相信这项研究为用 IRF5 抑制剂治疗 SLE 患者提供了首例体内临床支持。
