Молекулярные и клеточные механизмы воспаления при подагре: Molecular and cell mechanisms of inflammation in gout

Abstract

The review analyzes mechanisms of gouty inflammation and resolution of acute inflammation in gout and shows how their understanding contributes to creation of new technologies for the treatment of gout. The first part of the review addresses crystal-induced inflammation in gout, which is associated with activation of the NLRP3 inflammasome in macrophages. The crystal-induced inflammation consists of two stages, 1) synthesis of inflammasome components and 2) inflammasome assembly. The review analyzes signals activating the synthesis of inflammasome components, which are generated by the interaction of MSU (monosodium urate crystals) and macrophages. Stages of inflammation initiation are described, including the synthesis of inflammasome components, pro-caspases and pro-IL-1β. IL-1β is the main effector cytokine of gouty inflammation, which not only triggers the inflammatory response but also induces vasodilation, attraction of neutrophils to the place of crystal deposition, and even a greater potentiation of the acute inflammatory episode via the TLR-dependent activation of NF-κB (transcription factor). The role of soluble uric acid in the activation of NLRP3 inflammasomes is addressed. The main role in resolving acute gouty inflammation belongs to the same cells, macrophages and neutrophils, that contribute to the development of inflammation.The review focuses on signaling pathways switching the inflammatory response to inflammation resolution and termination, including the AMPK (AMP-activated kinase) signaling pathway, the TGFβ1, IL-10 and IL-1Ra anti-inflammatory cytokines, the protein annexin A1 (AnxA1), and α1-antitrypsin (AAT). The authors described in detail the techniques for therapeutic suppression of inflammation in gout using inflammasome and IL-1β inhibitors. Studying the mechanisms of gouty inflammation and its\xa0resolution has resulted in development of methods for reprogramming immune cells and adaptive immunotherapy of gout. These methods have already shown outstanding therapeutic potential for patients with other diseases such as cancer.