RAGE deficiency obstructs high uric acid-induced oxidative stress and inflammatory response.

Hyperuricemia is a metabolic disorder primarily associated with gout and implicated in various metabolic inflammatory diseases. While the role of monosodium urate crystals triggering inflammation has been well-documented, recent findings suggest that soluble high uric acid (HUA) also induces pro-inflammatory cytokine production in human monocytes. However, the comprehensive effects of HUA levels on macrophage dysfunction and the underlying mechanisms remain underexplored. This study employs urate oxidase knockout (UOX-KO) and receptor for advanced glycation end products deficiency (RAGE) mouse models to elucidate macrophage function and its mechanistic pathways. Our results demonstrate that HUA promotes M1 polarization and migration of macrophages while impairing their phagocytic ability. This process is mediated through the high mobility group box 1 (HMGB1)-RAGE- ROS axis. Notably, RAGE deficiency in bone marrow-derived cells partially mediates these effects. Pathologically, elevated HMGB1 and monocyte chemoattractant protein 1 levels in pancreatic islets increases macrophage infiltration in UOX-KO mice. Treatment with the FPS-ZM1, as a pharmacological RAGE inhibitor, effectively decreases serum UA levels, ameliorates islet inflammation and insulin resistance. These findings suggest that soluble HUA serves as a pro-inflammatory trigger through the HMGB1-RAGE-ROS axis, and that RAGE inhibition may mitigate these effects by decreasing inflammatory macrophage infiltration in the islets. Additionally, the influence of UA on macrophages extends beyond gout, potentially contributing to the pathogenesis of other metabolic inflammatory conditions, such as atherosclerosis, non-alcoholic steatohepatitis, obesity, and hyperlipidemia.