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

Abstract

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