Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation

Abstract

Leptin is an adipocytokine that plays a key role in the modulation of immune responses and the development and maintenance of inflammation. Circulating levels of leptin are elevated in systemic lupus erythematosus (SLE) patients, but it is not clear whether this association can reflect a direct influence of leptin on the propathogenic events that lead to SLE. To investigate this possibility, we compared the extent of susceptibility to SLE and lupus manifestations between leptin-deficient (ob/ob) and H2-matched leptinsufficient (wild-type, WT) mice that had been treated with the lupus-inducing agent pristane. Leptin deficiency protected ob/ob mice from the development of autoantibodies and renal disease and increased the frequency of immunoregulatory T cells (Tregs) compared with leptin-sufficient WT mice. The role of leptin in the development of SLE was confirmed in the New Zealand Black (NZB) × New Zealand White (NZW)F 1 (NZB/W) mouse model of spontaneous SLE, where elevated leptin levels correlated with disease manifestations and the administration of leptin accelerated development of autoantibodies and renal disease. Conversely, leptin antagonism delayed disease progression and increased survival of severely nephritic NZB/W mice. At the cellular level, leptin promoted effector T-cell responses and facilitated the presentation of self-antigens to T cells, whereas it inhibited the activity of regulatory CD4 T cells. The understanding of the role of leptin in modulating autoimmune responses in SLE can open possibilities of leptin-targeted therapeutic intervention in the disease.systemic lupus erythematosus | leptin | autoimmunity | immune regulation | animal models

Leptin in inflammation and autoimmunity

“…The propathogenic effects of leptin in SLE can be ascribed, at last in part, to its promoting activities on proinflammatory Th17 cells [27] and the facilitated autoantibody production that is concomitant to the inhibition of immunoregulatory responses [125]. Other mechanisms include leptin’s promotion of the activity and survival of autoreactive T cell via an increased expression of the anti-apoptotic molecule Bcl-2 [126–127].…”

“…Other mechanisms include leptin’s promotion of the activity and survival of autoreactive T cell via an increased expression of the anti-apoptotic molecule Bcl-2 [126–127]. Notably, leptin neutralization in lupus-prone mice inhibits proinflammatory responses and SLE manifestations [27, 125]. Similarly, a reduction in circulating leptin levels induced by fasting protects lupus mice from SLE via mechanisms that include an expansion of peripheral Tregs [128].…”

Fine tuning of immunometabolism for the treatment of rheumatic diseases

“…Sle1.Sle2.Sle3 mice spontaneously developed glucose intolerance without being fed a high-fat diet 82 . Whereas immune dysfunction might contribute directly to the sequelae of metabolic syndrome, such as atherosclerosis 83 , altered metabolic hormones and lipids can also modulate immunity, promoting B cell dysfunction 82 and effector T cell differentiation and function 84–86 .…”

Metabolic determinants of lupus pathogenesis

“…98 Likewise, leptin inhibited Treg cell polarization in vitro and its neutralization resulted in Treg cell expansion in NZB/W mice. 99 In this same study, leptin administration accelerated disease, whereas blocking leptin delayed disease progression. 99 Leptin deficiency in MRL/lpr mice also lowered serum IL-17 levels.…”