Genetic and Epigenetic Regulation of the Innate Immune Response to Gout

Gout is a disease caused by uric acid (UA) accumulation in the joints, causing inflammation. Two UA forms - monosodium urate (MSU) and soluble uric acid (sUA) have been shown to interact physically with inflammasomes, especially with the nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3), albeit the role of the immune response to UA is poorly understood, given that asymptomatic hyperuricemia does also exist. Macrophage phagocytosis of UA activate NLRP3, lead to cytokines release, and ultimately, lead to chemoattract neutrophils and lymphocytes to the gout flare joint spot. Genetic variants of inflammasome genes and of genes encoding their molecular partners may influence hyperuricemia and gout susceptibility, while also influencing other comorbidities such as metabolic syndrome and cardiovascular diseases. In this review, we summarize the inflammatory responses in acute and chronic gout, specifically focusing on innate immune cell mechanisms and genetic and epigenetic characteristics of participating molecules. Unprecedently, a novel UA binding protein - the neuronal apoptosis inhibitor protein (NAIP) - is suggested as responsible for the asymptomatic hyperuricemia paradox.