Background/Purpose:

Studies were performed to determine the significance of obesity in the pathogenesis of rheumatoid arthritis (RA) and experimental arthritis models.

Methods:

Chronic and acute preclinical models of arthritis were utilized to examine the impact of obesity on different disease stages. Inflammatory mediators were identified in RA and mouse adipose condition media using ELISA. Role of IL-8/MIP2 was investigated in disease onset employing neutrophil chemotaxis. RA and mouse myeloid cells as well as ankle joints from preclinical arthritis models were utilized to assess the importance of proinflammatory M1 macrophage differentiation in disease remission using real-time RT-PCR, histology and Western blotting.  

Results:

We document that early onset of collagen induced arthritis (CIA) was impacted by high fat diet (HFD) on days 26, 28 and 30 post onset compared to mice fed with  regular diet (RD). To elucidate the mechanism by which obesity affects the early stage of RA, inflammatory factors were quantified in adipose condition media extracted from RA synovial tissue and obese mouse gonadal adipose tissue. We uncovered that a great number of neutrophil (CXCL1, CXCL5 and IL-8/MIP2) and monocyte chemaoattractants (TNF-a, IL-17, IL-1b, CCL2) are present in RA and mouse adipose condition media, however levels of IL-8/MIP2 exceeded all other factors. We found that early arthritis exacerbated by obesity is due to elevated IL-8/MIP2 protein levels in the obese joint, as blockade of IL-8/MIP2 dysregulates neutrophil chemotaxis in response to RA and mouse adipose media, in contrast, neutralization of CXCL1 and CXCL5 was ineffective in this process. To elucidate the effect of obesity on arthritis progression, we chose to utilize the TLR4 induced arthritis model. We found that in the first 48h, TLR4 driven joint inflammation progresses similarly in obese and lean mice. Thereafter while arthritis resolves in the lean mice, ankle swelling is sustained in the obese mice at 72h post LPS injection. Histological studies confirm that mice on HFD have markedly greater joint inflammation and lining thickness compared to RD group. Corroborating with the higher levels of monocyte chemoattractants detected in the obese mice (TNF-a, IL-17, CCL20 and IL-6), joint myeloid cell recruitment was potentiated in the HFD arthritic mice compared to RD group. To better understand how obesity prolongs arthritis, joint myeloid cell phenotype was evaluated in the obese and the lean arthritic mice. We show that the obese arthritic mice, predominately express iNOS+ M1 macrophages; while iNOS+ cells are reduced and Arginase+ M2 macrophages are strongly expressed in the lean mice. Consistently, employing RA and mouse adipose condition media we show that RA or mouse naïve cells can be transformed into M1 macrophages. Hence, our results exhibit that obesity can sustain arthritis by reconstructing the newly recruited joint myeloid cells into proinflammatory M1 macrophages.    

Conclusion:

We show for the first time that early and late RA is impacted by obesity through differential mechanism of function.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-differential-impact-of-obesity-on-the-pathogenesis-of-ra-or-preclinical-models-is-contingent-on-the-disease-status/