Background/Purpose: Exercise was originally believed to exacerbate inflammation in rheumatic disease, however, recent studies have shown that regular physical activity is anti-inflammatory. In gout, there have been only a few pilot studies examining the effects of exercise on inflammation. Consequently, there are no exercise recommendations for gout patients in the clinical practice recommendations by the American College of Rheumatology (2012) and the American College of Physicians (2016). The objective of this study was to immunologically and mechanistically characterize the effects of different exercise intensities in a murine model of acute gout.

Methods:

Using a model of acute gout we previously developed using transgenic mice harboring an NFκB-luciferase reporter, we examined the effects of regular exercise at varying intensities on inflammation. Mice were exercised daily by treadmill walking (45 min/day for 2 weeks) at low intensity, moderate intensity, and high intensity and were subsequently injected with monosodium urate (MSU) crystals (0.5mg) into the tibio-tarsal joint (ankle). Localized NFκB activity was measured 16 hours later in the injected ankle via bioluminescent imaging and tissue was collected and processed for immunohistochemical (IHC) and immunofluorescent (IF) analysis. Expression of Toll-like receptor (TLR) 2/4 and chemokine receptors on peripheral monocytes and neutrophils was determined using flow cytometry. Serum was collected for systemic chemokine expression.

Results: Mice in the low/moderate intensity exercise groups had measurably less swelling and significantly less NFκB activity at the site of MSU crystal injection compared to the high-intensity group and non-exercised controls. Similarly, IHC of the synovial space of low/moderate intensity groups had decreased F4/80+ macrophages and MPO+ neutrophils relative to both high-intensity or non-exercised controls. Analysis by IF confirmed that both neutrophils and macrophages were secreting IL-1β in the ankle joints. Considering that MSU crystals, at least in part, induce their inflammatory response with activation of TLR2, surface expression was measured by flow cytometry on peripheral neutrophils and demonstrated a decrease of 17% in the low-intensity and 48% in the moderate-intensity groups. In concordance, localized IL-1β expression via IHC was reduced in low/moderate intensity exercise conditions. While there was little difference in chemokine receptor expression (CCR1, CCR2, CCR4, and CXCR2) on peripheral monocytes/neutrophils, the peripheral chemokine CXCL1 was significantly reduced with low and moderate exercise.

Conclusion: We hereby report that regular low/moderate intensity exercise regimens can reduce localized MSU crystal-induced inflammation, while high intensity training negates this response. An exercise-mediated suppression of NFκB activity and IL-1β expression locally can be explained, at least in part, by a reduction of TLR2 expression on peripheral neutrophils recruited to the site of inflammation and a down-regulation of CXCL1 expression.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/physical-activity-at-lower-intensities-reduces-localized-il-1b-in-a-murine-model-of-gout-by-systemically-down-regulating-tlr2-expression-on-circulating-neutrophils-and-suppressing-cxcl1-expression/