INHIBITION OF IRF5 HYPER-ACTIVATION PROTECTS FROM LUPUS ONSET AND SEVERITY
- Betsy J. Barnes, United States of America
Abstract
Background and Aims
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.
Methods
Buffy coats were prepared from fresh blood drawn from consented male and female healthy donors and SLE patients. SLE patients fulfilled at least four of the classification criteria for SLE as defined by the ACR. IRF5 activation was determined by imaging flow cytometry on an Amnis Imagestream X Mark II. In vivo studies were performed in NZB/W F1 and MRL/lpr models of murine lupus. IL6 and anti-dsDNA Ig levels were measure by ELISA. Proteinuria was measured by test strip and Bradford protein assay. Serum auto-antibodies were measured by ANA-HEp-2.
Results
In NZB/W F1 mice, we show that murine Irf5 is hyper-activated before clinical onset in a cell type-specific manner. In SLE patients, IRF5 hyper-activation correlated with SLEDAI and dsDNA titers. Treatment of NZB/W F1 and MRL/lpr mice with IRF5 inhibitor attenuated lupus pathology by reducing serum ANA and dsDNA titers, which alleviated kidney pathology and improved overall survival. In ex vivo human studies, inhibitor blocked SLE serum-induced IRF5 activation and reversed basal IRF5 hyper-activation in SLE immune cells.
Conclusions
Altogether, this study provides the first in vivo pre-clinical support for treating SLE patients with an IRF5 inhibitor.