Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 38, Pages 10637-10642Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1607101113
Keywords
systemic lupus erythematosus; leptin; autoimmunity; immune regulation; animal models
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Funding
- NIH [AR53239, AI109677]
- European Research Council (ERC) [310496]
- Italian Space Agency (ASI) [2014-033-R.O.]
- European Foundation for the Study of Diabetes/Juvenile Diabetes Research Foundation (EFSD/JDRF)/Lilly Programme
- European Foundation for the Study of Diabetes [JDRF Lilly 2015_4] Funding Source: researchfish
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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 H-2-matched leptin-sufficient (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) x 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.
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