Background/Purpose:   Better understanding of lipid metabolism in active rheumatoid arthritis (RA) is needed to understand the cholesterol changes associated with active disease, as well as the increases in cholesterol which occur with common RA treatments involving specific cytokine and chemokine pathways. In the current work we used both short and long term K/BxN mouse models of RA to evaluate the relationship between active RA, lipid measures (cholesterol levels/HDL efflux and anti-oxidant function) and serum cytokine/chemokine levels.

Methods:   29 K/BxN mice were generated from cross of male KRN mice with NOD female mice expressing the MHC class II molecule A^g7 and arthritis was assessed regularly until sacrifice/serum collection at 21 weeks. 15/29 mice received an atherogenic diet at 11 weeks until sacrifice. 18 C57BL/6 mice were injected intraperitoneally with either K/BxN serum (from 8 wk stock K/BxN mice) to induce inflammatory arthritis (n=9), or C57BL/6 serum as controls (n=9), and sacrifice/serum collection occurred at 2 weeks. Serum cytokine and chemokine levels were assessed using Luminex-based 20-plex assays. HDL’s cholesterol efflux and anti-oxidant functions were assessed as previously (ARD 2012; 71: 1157) and paraoxonase 1 (PON1) activity was assessed using both paraoxon and dihydrocumarin as substrates (A&R 2013; 65: 2765). Total and HDL cholesterol (HDL-C) were assessed by standard assays.

Results:   At 21 weeks, male mice (n=17) had significantly worse arthritis activity compared to female mice (n=12) which was associated with significantly higher levels of GM-CSF, IFN-γ, IL-1β, IL-6, IL-12, and FGF-basic, and significantly lower levels of HDL and total cholesterol and PON1 activity (Table 1). Impairment in the cholesterol efflux capacity of HDL was associated with significantly higher levels of GM-CSF, IFN-γ, IL-17, and FGF-basic which also correlated significantly with suppression of cholesterol levels and impairment in PON1 activity (Table 2). An atherogenic diet was not associated with significant changes in lipid assessments or cytokine/chemokine panels compared to chow diet.  Inflammatory arthritis of 2 weeks duration was not associated with a similar dyslipidemia or cytokine/chemokine changes.

Conclusion:  Increases in GM-CSF, IFN-γ, IL-1β, and FGF-basic in K/BxN mice with inflammatory arthritis of 21 weeks duration are associated with impairment in the cholesterol efflux capacity of HDL and suppression of PON 1 activity, total and HDL-C levels. Further investigation of these pathways including the effects on accelerated atherosclerosis in RA is warranted.   Table 1. Comparison of Female and Male K/BxN Mice at 21 weeks

*P<0.05 for comparison. IL-4, IL-5, IL-10, TNF-α, IP-10, MIG, MIP-1α, and VEGF assessed in the multiplex panel but values too low in majority of specimens to allow reliable analysis.     Table 2. Correlations of Arthritis and Lipid Assessments with Chemokine and Cytokine Levels

*p<0.05 for test of Spearman Correlation Coefficient. IL-4, IL-5, IL-10, TNF-α, IP-10, MIG, MIP-1α, and VEGF assessed in the multiplex panel but values too low in majority of specimens to allow reliable analysis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/suppression-of-cholesterol-levels-and-impairment-in-cholesterol-efflux-by-hdl-in-kbxn-mice-is-associated-with-a-specific-cytokinechemokine-profile/