Gout disorder is likely to be the most common cause of inflammatory arthritis. Hyperuricemia leads to formation of poorly soluble crystalline urate salts in tissues and joints, thus being etiological factor of the gout. The review summarizes modern views on the mechanisms of autoinflammation in gout disorder and it provides an outlook for the new treatment approaches. Inflammation in gout is related to phagocytosis of the urate crystals and the macrophagic NLRP3 inflammosome activation. This process consists of preliminary stage and proinflammatory cytokine generation phases. During the preliminary phase, soluble and crystalline urate salts initiate mRNA transcription for IL-1 and other proinflammatory cytokines precursors in macrophages, synthesis of NLRP3 inflammosome components, and formation of immune memory. Enhanced transcription of IL-1 and other cytokine precursors is implemented via PRAS49-AKT-mTOR signaling, IL- 1ra anti-inflammantory factor and TLR-MyD88-IRAK-NF-B pathway; the enhanced synthesis of NLRP3 inflammasome components provided via the TLR-NF-B pathway. The immune memory develops due to the epigenetic modifications, associated with (de-) acetylation and (de-) methylation of histones and DNA. During the next phase, the effect of soluble and crystalline urate salts upon macrophages promotes NLRP3 inflammosome activation, due to the following events: 1. К+, Cl- and Са2+ ionic currents shift; 2. lysosomic and mitochondrial damage, leading to the cathepsin B release and enhancement of reactive oxygen production, respectively; 3. NLRP3 relocation between the endoplasmic reticulum, Golgi complex and cytosol; 4. alteration of the NLRP3 structure due to auxiliary proteins attachment, phosphorylation, ubiquitination and acetylation. The NLRP3 inflammosome activity results into increased caspase 1 production which, in turn, produces IL-1 and pyroptotic pores proteins. The pyroptotic pores allow IL-1 passage, which further amplifies inflammation. During the pyroptosis, soluble and crystalline urate salts release from the cells, further increasing inflammation and tissue damage. Understanding the mechanisms of gout-associated inflammation helps us to formulate promising approaches to development of novel treatments. Macrophages are the key cells to crystal-induced inflammation development. Thus, new biothechnologies based on macrophage engineering may appear to be prospective in gout treatment. In this review, we have analyzed the prospects of M3 phenotype macrophages (AB-M3) usage in therapy, unlike M1 and M2 phenotypes, is able to produce anti-inflammatory cytokines in response to the inflammatory factors and, therefore, to inhibit crystal-induced inflammation. Meanwhile, unlike the anti-IL-1 medications, e.g., canakinumab, targeting a single end product of the gout inflammation (IL-1), AB-M3 macrophages inhibit not only IL-1 production, but also a group of other inflammatory cytokines.
