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Differential impact of obesity on the pathogenesis of RA or preclinical models is contingent on the disease status
  1. Seung-jae Kim1,2,
  2. Zhenlong Chen1,2,
  3. Abdul B Essani1,2,
  4. Hatem A Elshabrawy1,2,
  5. Michael V Volin3,
  6. Giamila Fantuzzi4,
  7. Iain B McInnes5,
  8. Joshua F Baker6,7,
  9. Patricia Finn8,
  10. George Kondos9,
  11. Suncica Volkov2,
  12. William Swedler1,2,
  13. Shiva Arami1,2,
  14. Nadera Sweiss1,
  15. Shiva Shahrara1,2
  1. 1Division of Rheumatology, Jesse Brown VA Medical Center, Chicago, Illinois, USA
  2. 2Division of Rheumatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
  3. 3Department of Microbiology & Immunology, Midwestern University, Downers Grove, Illinois, USA
  4. 4Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, USA
  5. 5Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
  6. 6Philadelphia VA Medical Center, Philadelphia, Pennsylvania, USA
  7. 7Division of Rheumatology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  8. 8Division of Pulmonary, Division of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
  9. 9Division of Cardiology, Division of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
  1. Correspondence to Dr Shiva Shahrara, University of Illinois at Chicago Department of Medicine, Division of Rheumatology 840 S. Woods Street, building CSB Room 1113/1114 Chicago, IL 60612, USA; shahrara{at}uic.edu

Abstract

Objective Studies were performed to uncover the significance of obesity in rheumatoid arthritis (RA) and preclinical models.

Methods Preclinical arthritis models were used to examine the impact of obesity on disease onset and remission. Conditioned media from RA adipose tissues were used to investigate the mechanism contributing to joint neutrophil influx and M1 macrophage differentiation observed in early and remission phases of arthritis.

Results We report that mice fed with high fat diet (HFD) have an earlier onset of collagen-induced arthritis (CIA) compared with mice on regular diet. However, the differences in CIA joint swelling between the two diet groups are lost once disease is established. We found that early arthritis triggered by obesity is due to elevated joint MIP2/interleukin-8 levels detected in CIA as well as in the RA and mouse adipose tissues and the effect of this chemokine on neutrophil recruitment. Although active disease progression is similarly affected in both diet groups, arthritis resolution is accelerated in lean mice while joint inflammation is sustained in obese mice. We document that HFD can prolong toll-like receptor (TLR)4-induced arthritis by increasing joint monocyte migration and further remodelling the recruited cells into M1 macrophages. Consistently, we show that adipose condition media can transform RA and wild-type naïve myeloid cells into M1 macrophages; however, this function is impaired by TLR4 blockade or deficiency.

Conclusions We conclude that despite established disease being unaffected by obesity, the early and the resolution phases of RA are impacted by obesity through different mechanisms.

  • Rheumatoid Arthritis
  • Chemokines
  • Inflammation
  • Cytokines
  • Early Rheumatoid Arthritis

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Footnotes

  • Handling editor Tore K Kvien

  • S-jK and ZC contributed equally.

  • Contributors All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. SS had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Designed the research: S-jK and SS. Performed the research: ZC, S-jK, ABE, MVV, HAE and SS. Analysed the data: ZC, S-jK, MVV, ABE, HAE, IBM, JFB, WS, SA, SV, NS, GF, GK, PF and SS. Provided essential reagents: WS, SA, SV and NS. Writing the paper: All the authors contributed to writing the paper.

  • Funding This work was supported in part by awards from Department of Veteran's Affairs MERIT Award 1I01BX002286, the National Institutes of Health AR055240 and AR065778, grant from Within Our Reach from the ACR, funding provided by Department of Defense PR093477 and Arthritis Foundation Innovative award. JFB efforts were funded by VA clinical science research and development as well as VA Career Development Award IK2 CX000955.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Approved by Local Ethical Committees.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All data have been included in the paper.

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