IRF5 Deficiency Ameliorates Lupus but Promotes Atherosclerosis and Metabolic Dysfunction in a Mouse Model of Lupus-Associated Atherosclerosis

Abstract

Premature atherosclerosis is a severe complication of lupus and other systemic autoimmune disorders. Gain-of-function polymorphisms in interferon regulatory factor 5 (IRF5) are associated with an increased risk of developing lupus and IRF5 deficiency in lupus mouse models ameliorates disease. However, whether IRF5 deficiency also protects against atherosclerosis development in lupus is not known. Here we addressed this question using the gld.apoE−/− mouse model. IRF5 deficiency markedly reduced lupus disease severity. Unexpectedly, despite the reduction in systemic immune activation, IRF5-deficient mice developed increased atherosclerosis and also exhibited metabolic dysregulation characterized by hyperlipidemia, increased adiposity and insulin resistance. Levels of the atheroprotective cytokine IL-10 were reduced in aortae of IRF5-deficient mice and in vitro studies demonstrated that IRF5 is required for IL-10 production downstream of TLR7 and TLR9 signaling in multiple immune cell types. Chimera studies showed that IRF5 deficiency in bone marrow-derived cells prevents lupus development and contributes in part to the increased atherosclerosis. Notably, IRF5 deficiency in non-bone marrow-derived cells also contributes to the increased atherosclerosis through the generation of hyperlipidemia and increased adiposity. Together, our results reveal a protective role for IRF5 in lupus-associated atherosclerosis that is mediated through the effects of IRF5 in both immune and non-immune cells. These findings have implications for the proposed targeting of IRF5 in the treatment of autoimmune disease as global IRF5 inhibition may exacerbate cardiovascular disease in these patients.

Fungal pattern receptors down‐regulate the inflammatory response by a cross‐inhibitory mechanism independent of interleukin‐10 production

“…Taken collectively, experiments showed that the function of IRF5 is complex and may be cell‐ and stimulus‐dependent. A recent report showed that IRF5 is necessary for IL‐10 production in response to TLR7 and TLR9 stimulation in mouse GM‐CSF macrophages and DC, whereas the response to TLR2 and TLR4 ligands did not reach statistical significance, although it was lower in Irf5 −/− mice . In summary, we observed a robust activation of STAT3 and production of IL‐10 in human and mouse DC stimulated with zymosan that depends on its mannose‐based component.…”

Toll-like receptor 7 deficiency protects apolipoprotein E-deficient mice from diet-induced atherosclerosis

“…In lupus-prone Fasl gld/gld Apoe −/− mice, deficiency of IRF5 increased aortic root and arch lesion area and plasma levels of triglyceride, cholesterol, phospholipids, and non-esterified fatty acids, with concurrent reduction of plasma IL10 levels. Bone marrow macrophages from IRF5-deficient mice also showed reduced IL10 production in response to TLR7 ligands R848 or R837 26 . Therefore, the exact role of TLR7 in atherosclerosis remains uncertain and may depend on different experimental model systems.…”

Update on cardiovascular disease in lupus

“…For example, while IRF5 appears to be implicated in lupus pathogenesis, it appears to have a protective role in lupus-associated atherosclerosis through effects on both immune and nonimmune cells. (16)*…”

“…(15)* Furthermore, murine models suggest a synergism between genes that promote atherogenesis with those that promote autoimmunity, although the relationship between enhanced plaque and more profound systemic immune dysregulation requires further elucidation. (16)*…”