Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 174, Issue 18, Pages 3018-3031Publisher
WILEY
DOI: 10.1111/bph.13932
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Funding
- Pfizer Investigator Initiated Research (IIR) Competitive Grant (ASPIRE) [XZJ-IIR-01-1]
- Instituto de Salud Carlos III [PI13/00570, PI15/00340, PI16/00065, RETICEF RD12/0043/0008]
- Fondo Europeo de Desarrollo Regional (FEDER)
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Background and PurposePatients 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 ApproachCA 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 (10mgkg(-1)day(-1)) for 2weeks. 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 IFN in the presence or absence of tofacitinib in order to study mediators of RCT. Key ResultsTofacitinib 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, IFN 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 and ATP-binding cassette transporter (ABCA1) synthesis. Conclusions and ImplicationsActive 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.
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