![]() In recent years, accumulating evidence has illustrated that Drp1 is implicated in the activation of NLPR3 inflammasome, and plays a crucial role in a variety of inflammatory disorders. Identification of novel therapeutic target is needed to improve the clinical outcomes in gouty arthritis.ĭynamin-related protein 1 (Drp1) is recognized as the master regulator of mitochondrial fission. In addition, the pro-oxidant, in particular mitochondrial reactive oxygen species (ROS), is also known to activate NLRP3 inflammasome. IL-1β further induces neutrophil articular infiltration, leading to joint pain. MSU crystals are taken up by macrophages and trigger the NLRP3 inflammasome activation, as well as the maturation and release of IL-1β. Compelling evidence has illustrated the key roles of NLRP3 inflammasome and the pro-inflammatory cytokine IL-1β in gouty arthritis. MSU crystals elicit inflammatory response which is principally mediated by macrophages and neutrophils. The precipitation of monosodium urate (MSU) crystals within joints is a well-accepted cause of gouty arthritis. Higher prevalence of gout has been observed in China, and the rising incidence and prevalence of gout have been found by each decade of life. Gouty arthritis is the most frequently diagnosed inflammatory arthritis globally. Conclusionĭeubiquitinase USP16 induced gouty arthritis via Drp1-dependent mitochondrial fission and NF-κB/NLRP3 signaling. Functional studies further showed that USP16 was highly expressed in MSU-stimulated macrophages and induced gouty arthritis via Drp1-dependent NLRP3 inflammasome activation. Mechanistically, USP16 mediated deubiquitination and stabilization of Drp1 through its direct interaction with Drp1. In addition, Drp1 activated NF-κB/NLRP3 signaling via modulating mitochondrial fission. Resultsĭrp1 was elevated in MSU-induced gouty arthritis model, and it induced gouty arthritis via NF-κB pathway and NLRP3 inflammasome activation. Co-IP and GST pull-down assay were used to detect the direct interaction between USP16 and Drp1, as well as the ubiquitination of Drp1. Mitochondrial structure and functions were assessed by transmission electron microscopy (TEM) and MitoSOX staining. Cytokine secretion was measured by ELISA assay, and antioxidant enzymes activities and LDH release were monitored using commercial kits. RT-qPCR and western blot were used to detect the expression of Drp1 and the key molecules in joint tissues and macrophages. Histological changes were assessed by H&E and IHC analysis. MethodsĪ mouse model of monosodium urate (MSU)-induced gouty arthritis and MSU-stimulated macrophages were established as in vivo and in vitro models, respectively. However, the biological role of Drp1 in gouty arthritis remains undefined. Dynamin-related protein 1 (Drp1), a regulator of mitochondrial fission, contributes to various inflammatory disorders via activating NLRP3 inflammasome. Gouty arthritis is the most frequently diagnosed inflammatory arthritis worldwide. ![]()
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