Delayed resolution of acute inflammation during zymosan-induced arthritis in leptin-deficient mice

Background

Proinflammatory or anti-inflammatory roles have been ascribed to leptin, depending on the experimental model investigated. We recently observed decreased severity of antigen-induced arthritis (AIA) in leptin-deficient ob/ob mice. However, joint inflammation in AIA depends on the immune response to an exogenous antigen, which is impaired in ob/ob mice.

Objective

The aim of the present study was to investigate potential effects of leptin in zymosan-induced arthritis (ZIA), a model of acute inflammatory arthritis, which is not dependent on the adaptive immune response.

Methods and results

Arthritis was induced in ob/ob and control +/? C57BL/6 mice by injection of zymosan A (Zy) into the knee joint cavity. Increased blood flow, reflecting the severity of joint inflammation, was quantified by uptake of technetium 99 m. It was similar 6 and 24 hours after Zy injection in ob/ob and control mice. However, it persisted on day 3 in ob/ob animals, while subsiding in controls. Histology repeatedly showed similar severity of arthritis in ob/ob mice and controls on day 3, but arthritis always tended to be more severe in ob/ob than in +/? mice at later time points (days 14 and 21). Similar observations were made using leptin-receptor-deficient db/db mice, suggesting that the effects of leptin are mediated via the Ob-Rb receptor. The acute-phase response was examined in ob/ob and control mice after injection of Zy by measuring circulating levels of interleukin (IL)-6 and serum amyloid A (SAA). Serum IL-6 increased in all animals during the first 24 hours after Zy injection, but IL-6 levels were significantly higher in ob/ob mice than in controls. SAA increased in all animals during the first 3 days after Zy injection, but SAA levels were significantly higher on days 1 and 3 in ob/ob animals than in controls. The acute-phase response thus appeared to be more pronounced in ob/ob mice, although corticosterone levels were significantly elevated in these animals at baseline and throughout the experiment

Conclusion

These data suggest that the resolution of acute inflammation during ZIA is delayed in leptin-deficient animals. In this model, leptin thus appears to display anti-inflammatory properties, limiting the acute phase response and the chronicity of arthritis.