Tofacitinib restores the inhibition of reverse cholesterol transport induced by inflammation: understanding the lipid paradox associated with rheumatoid arthritis

BACKGROUND AND PURPOSE Patients with active rheumatoid arthritis (RA) have increased cardiovascular mortality, paradoxically associated with reduced circulating lipid levels. The Janus kinase (Jak) inhibitor tofacitinib ameliorates systemic and joint inflammation in RA with a concomitant increase in serum lipids. We analyzed the effect of tofacitinib on the lipid profile of hyperlipidemic rabbits with chronic arthritis (CA) and on the regulation of reverse cholesterol transport (RCT) during chronic inflammation. EXPERIMENTAL APPROACH CA was induced in previously immunized rabbits fed with a high-fat diet (HFD) by administering four intra-articular injections of ovalbumin. A group of rabbits received tofacitinib (10 mg kg-1 day-1) for two weeks. Systemic and synovial inflammation and lipid content were evaluated. For in vitro studies, THP-1-derived macrophages were exposed to high lipid concentrations, and then stimulated with interferon gamma (IFNγ) in the presence or absence of tofacitinib in order to study RCT mediators. KEY RESULTS Tofacitinib decreased systemic and synovial inflammation and increased circulating lipid levels. Although it did not modify synovial macrophage density, it was able to reduce the lipid content within synovial macrophages. In foam macrophages in culture, IFNγ further stimulated intracellular lipid accumulation, while Jak/STAT inhibition provoked by tofacitinib induced lipid release by increasing cellular liver X receptor alpha (LXRα) and ATP-binding cassette transporter (ABCA1) synthesis. CONCLUSION AND IMPLICATIONS Active inflammation could be associated with lipid accumulation within macrophages of CA rabbits. Jak inhibition induced lipid release though RCT activation, providing a plausible explanation for the effect of tofacitinib on the lipid profile of RA patients.