The Peroxisome Proliferator-Activated Receptor γ Agonist Rosiglitazone Ameliorates Murine Lupus by Induction of Adiponectin

Abstract

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease for which current therapy is suboptimal. SLE is characterized by autoantibody production, with renal disease and premature atherosclerosis being common and severe manifestations causing appreciable morbidity and mortality. Peroxisome proliferator-activated receptor γ (PPARγ) agonists are widely used in the treatment of diabetes mellitus for their insulin-sensitizing properties, but also have immunomodulatory effects. In this report, we show that the PPARγ agonist rosiglitazone reduces autoantibody production, renal disease, and atherosclerosis in mouse models of SLE. The beneficial effect of rosiglitazone on SLE manifestations depends on the induction of adiponectin, because rosiglitazone has no effect on autoantibody production or renal disease in lupus mice that lack adiponectin. In addition, lupus mice that lack adiponectin develop more severe disease than adiponectin-sufficient lupus mice, indicating that endogenous adiponectin is involved in regulating disease activity. Furthermore, administration of exogenous adiponectin ameliorates disease. These experiments suggest that PPARγ agonists may be useful agents for the treatment of SLE. They also demonstrate that induction of adiponectin is a major mechanism underlying the immunomodulatory effects of PPARγ agonists.

Peroxisome Proliferator-activated Receptor γ Negatively Regulates IFN-β Production in Toll-like Receptor (TLR) 3- and TLR4-stimulated Macrophages by Preventing Interferon Regulatory Factor 3 Binding to the IFN-β Promoter

“…Considering the involvement of IFN-␤ in several pathogenic autoimmune diseases, our results suggest that PPAR-␥ agonists may have therapeutic potential to cure these diseases. In accordance with our results, recent studies have shown that PPAR-␥ agonists could ameliorate murine lupus in a mouse model of SLE (22,23).…”

Rosiglitazone decreases blood pressure and renal injury in a female mouse model of systemic lupus erythematosus

“…Previously published work from Gilkeson and colleagues showed that the lupus-prone MRL/lpr mice exhibit a reduction in renal mesangial cell PPAR␥ expression (13), making it tempting to postulate that a reduction in PPAR␥ expression and activity could, in part, contribute to SLE hypertension and renal injury. While this study was under consideration for publication, Rifkin and colleagues reported that treatment of the MRL/lpr model of SLE with rosiglitazone reduced glomerular area and cellularity (2). The authors demonstrate, using MRL/lpr-adiponectin knockout mice, that the protective actions of rosiglitazone occur through activation of adiponectin.…”

Cardiometabolic comorbidities and rheumatic diseases: Focus on the role of fat mass and adipokines

“…It has been reported that adiponectin acts as a negative modulator of the autoimmune phenotype in a murine model of lupus, and this effect is more pronounced in female versus male mice (108). It was also reported that mice with lupus that lack adiponectin develop more severe disease than wild-type mice, which suggested that adiponectin is involved in regulating disease activity (109). Moreover, the same authors also reported that the beneficial effects of peroxisome proliferator-activated receptor ␥ agonist (rosiglitazone), by reducing autoantibody production, renal disease, and atherosclerosis in a mouse model of SLE, are mainly supported by adiponectin induction (109).…”