The role of interferon regulatory factor-5 in systemic lupus erythematosus (SLE) and SLE-associated atherosclerosis
Watkins, Amanda Ann
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Gain-of-function polymorphisms in the gene encoding human interferon regulatory factor-5 (IRF5) are associated with an increase in risk for the development of the autoimmune disease Systemic Lupus Erythematosus (SLE). IRF5 is a transcription factor that participates in the activation of the immune system through its role in both innate and adaptive immune cells. To determine the role of IRF5 in lupus pathogenesis in vivo, we evaluated the effect of Irf5-deficiency in the MRL/lpr mouse lupus model. We find that Irf5-deficient (Irf5-/-) MRL/lpr mice develop much less severe disease than their Irf5-sufficient (Irf5+/+) littermates, demonstrating an important role for IRF5 in disease pathogenesis in vivo. Patients with SLE are at increased risk for the development of atherosclerosis due in large part to poorly-defined lupus-specific risk factors. One such lupus-specific risk factor is thought to be chronic inflammation associated with the autoimmune process. As IRF5 is involved in pro-inflammatory responses we hypothesized that Irf5-deficiency would ameliorate atherosclerosis development in the context of autoimmunity. We therefore examined the role of IRF5 in the gld.apoE-/- mouse model of lupus and lupus-associated atherosclerosis. Irf5-deficiency led to a decrease in splenomegaly, lymphadenopathy, anti-nuclear autoantibody production and the severity of kidney disease. Surprisingly, despite the reduction in systemic autoimmunity, Irf5-deficiency led to a marked increase in the severity of atherosclerosis and to metabolic dysregulation characterized by hyperlipidemia, increased adiposity and insulin-resistance. Bone marrow chimera studies revealed that the pathogenic role of IRF5 in lupus was solely due to its expression in hematopoietic cells. The atheroprotective effect of Irf5 and the suppression of adiposity were found to be due to Irf5 expression in both hematopoietic and non-hematopoietic cells, whereas protection from hyperlipidemia was solely due to the expression of Irf5 in non-hematopoietic cells. Together, our results reveal a role for IRF5 in metabolic homeostasis, as well as in protection against atherosclerosis even in the setting of reduced lupus severity.