Abstract
Gout is driven by an interleukin-1β-mediated intense innate immune reaction to monosodium urate (MSU) crystals (MSUc). In cell culture models of inflammatory gout there is a synergistic effect of phagocytosis of MSUc and TLR2 and TLR4 activation by agonists such as free fatty acid and lipopolysaccharide (LPS) in NLRP3-inflammasome activation and IL-1β secretion. A substantial number of gout patients do not report a dietary trigger, and observational studies associate airborne particulate matter with incident gout and flares. Airborne particulate matter contains LPS and airborne-derived particulate matter stimulates IL-1β secretion in cell culture. We hypothesized that air-borne particulate matter could co-stimulate, with MSUc, IL-1β secretion and inflammation. We tested the hypothesis using MSUc with extracted airborne PM(4) in human cells (the THP-1 monocyte cell line, primary human monocytes and PBMCs) or carbon black particles with ozone (CB+O(3)) in a murine foot-pad injection model of gout. There was strong NLRP3-inflammasome-dependent co-stimulation of IL-1β secretion in THP-1 cells with PM(4)+MSUc and a moderate additive effect in primary human PBMCs. However, there was no added effect on IL-1β secretion of PM(4) in isolated primary human monocytes. Inhalation of CB+O(3) persistently exacerbated MSUc-induced murine paw inflammation, with an increase of alveolar/lavage macrophages that contained CB+O(3) particles and increased lavage expression of IL-1β. In conclusion, airborne-derived PM(4) particulate matter enhanced MSUc-induced IL-1β secretion in THP-1 cells and PBMCs. Combined with exacerbation of MSUc-induced inflammation by fine particulate matter in in vivo experiments, these data provide evidence that exposure to fine particulate matter may play a role in the etiology of gout.