Article Text

Download PDFPDF

FRI0071 Tofacitinib restores the inhibition of reverse cholesterol transport induced by inflammation: understanding the lipid paradox associated with rheumatoid arthritis
Free
  1. S Pérez Baos,
  2. JI Barrasa,
  3. P Gratal,
  4. A Larrañaga-Vera,
  5. I Prieto-Potin,
  6. G Herrero-Beaumont,
  7. R Largo
  1. Bone and Joint Research Unit, Rheumatology Dept., IIS-Fundaciόn Jiménez Díaz UAM, Madrid, Spain

Abstract

Background Patients with active rheumatoid arthritis (RA) have increased cardiovascular mortality, paradoxically associated with reduced serum lipid levels. In fact, an inverse relationship between C-reactive protein (CRP) and circulating lipid levels has been observed [1,2]. The Jak inhibitor tofacitinib ameliorates systemic and joint inflammation in RA with a concomitant increase in serum lipids [3].

Objectives Our aim was to analyze the effect of tofacitinib on the lipid and inflammatory profile of hyperlipidemic rabbits with chronic arthritis (CA), and on the regulation of reverse cholesterol transport (RCT) during chronic inflammation.

Methods New Zealand male rabbits were randomly assigned to three groups: control group (n=6), chronic arthritic rabbits (CA, n=9) and CA rabbits receiving tofacitinib (CA+TOFA, n=9). All animals were fed ad libitum with a high-fat diet (0.5% cholesterol, 4% peanut oil). CA was induced in previously immunized rabbits by administering four intra-articular injections of ovalbumin. A group of rabbits received tofacitinib (10mg/kg/day) for two weeks. All animals were euthanized 6 weeks after challenge, when synovial and serum samples were collected. For in vitro studies, vehicle and ABCA1 siRNA-treated 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 assess their cholesterol efflux capacity and the involved mediators.

Results CA rabbits showed lower levels of serum TC and LDL-C compared to controls (p=0.001, p=0.012), while TC/HDL-C ratio was higher in CA+TOFA rabbits when compared to CA animals (150±15 vs 231±17, p=0.004). Synovial inflammation and CRP levels were increased in CA animals, and a significant reduction was shown in CA+TOFA rabbits in both parameters. We also observed an inverse correlation between serum TC and CRP (R=-0.454, p=0.029). Tofacitinib was able to reduce the lipid content within synovial macrophages up to a 58% (p=0.041), although it did not modify synovial macrophage density. In foam macrophages in culture, an inflammatory milieu induced by IFNγ further stimulated the intracellular lipid accumulation (p=0.041) along with a decrease in the protein levels of the nuclear factor LXRα (liver X receptor α) and the cholesterol transporter ABCA1 (ATP-binding cassette transporter 1) (p=0.002 and p=0.0047, respectively). Tofacitinib prevented the lipid accumulation within macrophages (p=0.029) by increasing LXRα (p=0.047) and ABCA1 synthesis (p=0.004) in a Jak/STAT-dependent manner, while it was unable to reduce lipid accumulation in ABCA1 silenced macrophages.

Conclusions Our results suggest that active inflammation could be associated with lipid accumulation within macrophages – in the synovium and probably in other tissues – thus inducing a decrease in serum lipid levels. Tofacitinib may prevent this phenomenon, at least partially, by increasing RCT pathways in macrophages. Taken together, these findings further explain how serum lipid levels are diminished in RA and partially justify the effect of tofacitinib on the lipid profile in RA patients.

References

  1. Choy E, Sattar N. Ann Rheum Dis 2009;68:460–9.

  2. Johnsson H et al. Ann Rheum Dis 2013;73:1495–9.

  3. van Vollenhoven RF et al. N Engl J Med 2012;367:508–19.

References

Disclosure of Interest None declared

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.