The effect of diet-induced obesity on the inflammatory phenotype of non-adipose-resident macrophages in an in vivo model of gout.

Abstract

Gout is strongly associated with obesity. The aim of this study was to determine if obesity altered the inflammatory phenotype of non-adipose tissue-resident macrophages in response to the gout-causing agent monosodium urate (MSU) crystals. C57BL/6J mice were fed a high-fat diet for 12 weeks. Resident peritoneal macrophages were stimulated ex vivo with MSU crystals (200 µg/ml for 18 h) and the supernatants were collected. Mice were challenged with MSU crystals in vivo (3 mg, intraperitonal) and the peritoneal lavage fluid was collected (8 and 16 h). Cytokine and chemokine levels were analysed by multiplex bead array and peritoneal cell populations were analysed by flow cytometry. Peritoneal macrophages from obese mice produced elevated background levels of IL-6, monocyte chemoattractant protein 1 (MCP-1) and keratinocyte-derived cytokine (KC) that decreased following MSU crystal stimulation ex vivo. MSU-induced IL-1β production was higher for macrophages from obese mice compared with controls. High background levels of IL-6, MCP-1, KC and GM-CSF, but not IL-1β, were measured in the peritoneal fluid of unchallenged obese mice. MSU crystal challenge in vivo raised IL-1β levels equally in both control and obese mice, whereas elevated background levels of IL-6, MCP-1, KC and GM-CSF levels dropped in obese mice. There was a consistent trend towards lower numbers of naive peritoneal resident macrophages and MSU-recruited monocytes and neutrophils in obese mice. Obesity induces a background pro-inflammatory environment orchestrated by non-adipose tissue-resident macrophages. However, this may not automatically translate into exacerbation of MSU crystal-induced inflammation in gout.