Immune-phenotyping IRF5 genetic risk and in vivo targeting of Irf5 hyper-activation in mouse models of lupus

Abstract

Abstract Genetic variations within interferon regulatory factor 5 (IRF5) associate with risk of systemic lupus erythematosus (SLE) and mice lacking Irf5 are protected from lupus onset and severity. Exactly how IRF5 functions in the context of SLE disease progression remains unclear. We sought to determine how IRF5 genetic risk contributes to SLE disease onset and severity, and whether targeting IRF5 with select inhibitors would alleviate disease severity and mortality. Studies were performed in blood from genotyped healthy donors, SLE patients and mouse models of murine lupus. In NZB/W F1 lupus mice, we found that Irf5 is already hyper-activated before clinical onset in a cell type-specific manner. In healthy donors carrying IRF5 genetic risk, we detected IRF5 hyper-activation in the myeloid compartment that drives a pre-symptomatic SLE immune-phenotype. In SLE patients, IRF5 hyper-activation correlates with SLEDAI and 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. Treatment of NZB/W F1 and MRL/lpr mice with inhibitor attenuated lupus pathology by reducing serum ANA and dsDNA titers. In NZB/W F1 mice, we detected significant reductions in the number of circulating plasma cells and age- or autoimmune-associated B cells (ABCs), which alleviated kidney pathology and improved overall 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. This study provides the first in vivo pre-clinical support for treating SLE patients with an IRF5 inhibitor.