The transcription factor interferon regulatory factor 5 (IRF5) is a central mediator of innate and adaptive immunity. Genetic variations within IRF5 associate with 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 hyper-activated before clinical onset. In SLE patients, IRF5 hyper-activation correlated with dsDNA titers. To test whether IRF5 hyper-activation is a targetable function, we developed novel inhibitors that are cell permeable, non-toxic and selectively bind to the inactive IRF5 monomer. Preclinical treatment of NZB/W F1 mice with inhibitor attenuated lupus pathology by reducing serum ANA, dsDNA titers and the number of circulating plasma cells, which alleviated kidney pathology and improved survival. Clinical treatment of MRL/lpr and pristane-induced mice with inhibitor led to significant reductions in dsDNA levels and improved survival. In ex vivo human studies, the inhibitor blocked SLE serum-induced IRF5 activation in healthy immune cells and reversed basal IRF5 hyper-activation in SLE immune cells. Altogether, this study provides the first in vivo clinical support for treating SLE patients with an IRF5 inhibitor.
Su Song, Saurav De, Victoria Nelson, Samin Chopra, Margaret LaPan, Kyle Kampta, Shan Sun, Mingzhu He, Cherrie D. Thompson, Dan Li, Tiffany Shih, Natalie Tan, Yousef Al-Abed, Eugenio Capitle, Cynthia Aranow, Meggan Mackay, William L. Clapp, Betsy J. Barnes