A critical link between Lyn-mediated suppression of the TLR-MyD88-IRF5 pathway and the development of SLE-like disease

• DOI: 10.4049/jimmunol.196.supp.48.4
• Publication Date: 2023-01-01T10:43:51Z
• Authors: Tatsuma Ban; Go Sato; Akira Nishiyama; Ai Akiyama; Marie Takasuna; Marina Umehara; Shinsuke Suzuki; Motohide Ichino; Satoko Matsunaga; Ayuko Kimura; Yayoi Kimura; Hideyuki Yanai; Sadakazu Miyashita; Junro Kuromitsu; Kappei Tsukahara; Kentaro Yoshimatsu; Itaru Endo; Tadashi Yamamoto; Hisashi Hirano; Akihide Ryo; Tadatsugu Taniguchi; Tomohiko Tamura
• Keywords: LYN; IRF5; TLR7

Abstract The transcription factor interferon regulatory 5 (IRF5) is critical for innate immune responses downstream of Toll-like receptors (TLRs). IRF5 also linked to the pathogenesis systemic lupus erythematosus (SLE) in humans and mice. However, it remains elusive whether how activity can be negatively regulated. Src family kinase Lyn implicated human SLE, Lyn−/− mice develop an SLE-like disease. Here we show that selectively inhibits activity, while does not affect NF-κB pathway. physically interacted with IRF5, thereby suppressing phosphorylation ubiquitination post-translational modifications important activation. Interestingly, was dispensable suppression activity. hyper-activated TLR7/9-stimulated bone marrow-derived dendritic cells (BMDCs), these hyper-produced IRF5-dependent cytokines especially type-I interferons (IFNs). constitutively activated (phosphorylated translocated into nucleus) splenic DCs isolated from Importantly, even monoallelic ablation Irf5 gene sufficient alleviate hyper-production IFNs BMDCs, ameliorate development symptoms, such as autoantibody production autoimmune glomerulonephritis, Our results identify a suppressor TLR-MyD88-IRF5 pathway, implicate selective control may contribute better therapeutics SLE.