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

Article date: September 2017

By: S Pérez‐Baos, J I Barrasa, P Gratal, A Larrañaga‐Vera, I Prieto‐Potin, G Herrero‐Beaumont, R Largo in Volume 174, Issue 18, pages 3018-3031

Background and Purpose

Patients with active rheumatoid arthritis (RA) have increased cardiovascular mortality, paradoxically associated with reduced circulating lipid levels. The JAK inhibitor tofacitinib ameliorates systemic and joint inflammation in RA with a concomitant increase in serum lipids. We analysed the effect of tofacitinib on the lipid profile of hyperlipidaemic rabbits with chronic arthritis (CA) and on the changes in reverse cholesterol transport (RCT) during chronic inflammation.

Experimental Approach

CA was induced in previously immunized rabbits, fed a high‐fat diet, by administering four intra‐articular injections of ovalbumin. A group of rabbits received tofacitinib (10 mg·kg−1·day−1) for 2 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 IFNγ in the presence or absence of tofacitinib in order to study mediators of RCT.

Key Results

Tofacitinib decreased systemic and synovial inflammation and increased circulating lipid levels. Although it did not modify synovial macrophage density, it reduced the lipid content within synovial macrophages. In foam macrophages in culture, IFNγ further stimulated intracellular lipid accumulation, while the JAK/STAT inhibition provoked by tofacitinib induced lipid release by increasing the levels of cellular liver X receptor α and ATP‐binding cassette transporter (ABCA1) synthesis.

Conclusions and Implications

Active inflammation could be associated with lipid accumulation within macrophages of CA rabbits. JAK inhibition induced lipid release through RCT activation, providing a plausible explanation for the effect of tofacitinib on the lipid profile of RA patients.

DOI: 10.1111/bph.13932

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