Peroxisome proliferator‐activated receptor gamma agonists in the prevention and treatment of murine systemic lupus erythematosus

Abstract

Summary Peroxisome proliferator‐activated receptor gamma (PPARγ) agonists are known to have many immunomodulatory effects. We have previously shown that the PPARγ agonist rosiglitazone is beneficial when used early in prevention of disease in murine models of systemic lupus erythematosus (SLE) and SLE‐related atherosclerosis. In this report, we demonstrate that another PPARγ agonist, pioglitazone is also beneficial as a treatment for early murine lupus, indicating that this is a class effect and not agent‐specific. We further attempt to define the ability of PPARγ agonists to ameliorate established or severe autoimmune disease using two mouse models: the MRL.lpr SLE model and the gld.apoE−/− model of accelerated atherosclerosis and SLE. We demonstrate that, in contrast to the marked amelioration of disease seen when PPARγ agonist treatment was started before disease onset, treatment with rosiglitazone after disease onset in MRL.lpr or gld.apoE−/− mice had minimal beneficial effect on the development of the autoimmune phenotype; however, rosiglitazone treatment remained highly effective at reducing lupus‐associated atherosclerosis in gld.apoE−/− mice after disease onset or when mice were maintained on a high cholesterol Western diet. These results suggest that beneficial effects of PPARγ agonists on the development of autoimmunity might be limited to the early stages of disease, but that atherosclerosis, a major cause of death in SLE patients, may be ameliorated even in established or severe disease.

Single-nucleotide polymorphisms of peroxisome proliferator-activated receptor-γ are associated with systemic lupus erythematosus in a Chinese Han population

“…A recent study suggested that PPAR‐γ agonists could be used in the prevention and treatment of murine SLE. Oxer et al .…”

LXR, PPAR<i>γ</i>, and PPAR<i>δ</i> Agonists Are Not Sufficient to Demonstrate Therapeutic Potential against Mouse Model of Systemic Lupus Erythematosus

“…We also tested the efficacy of LXR Recent work suggested that PPARγ agonist treatment started before disease onset demonstrated the marked amelioration of disease, while it was not effective when started after disease onset [8]. We thought that the administration of LXR or PPARγ/δ agonists at 8 weeks of age might be too late to suppress the disease and we administered them immediately after the injection of pristane in BALB/c mice; however, they did not reveal the beneficial effects in prevention.…”

PPARs and the Development of Type 1 Diabetes

“…It is involved in regulating fat cell differentiation, lipid storage, and differentiation of monocytes into macrophages [32,33]. PPARs have, due to their immune regulatory functions, been linked to several autoimmune diseases, i.e., multiple sclerosis [34], lupus erythematosus [35], autoimmune thyroiditis [36], Graves ophthalmopathy [37], rheumatoid arthritis [38], psoriasis [39], and Guillain-Barré [40]. Similarly, PPARs have also been suggested as targets to treat chronic inflammatory diseases [20,41].…”