POS0136\u2005ROLES OF AUTOPHAGY IN THE PATHOGENESIS OF PRIMARY GOUTY ARTHRITIS

Abstract

Gout is a chronic autoinflammatory disease caused by monosodium urate (MSU) crystal deposition [1].Acute gout is characterized by an acute inflammatory reaction that resolves spontaneously within a few days[2], which is one of the distinguishing features of gout compared to other arthropathies or self-inflammatory diseases. Autophagy is a lysosomal degradation pathway that is essential for cellular growth, survival, differentiation, development and homeostasis [3]. Studies have demonstrated that autophagy might play a key role in the pathogenesis of primary gouty arthritis (GA) [4-7]. However, the roles of autophagy in the development of gout have not yet been elucidated.The aim of our study was to investigate the changes in autophagy-related gene (ATG) mRNA and protein in patients and the clinical importance of these genes in primary gouty arthritis (GA) and to explore the roles of autophagy in the pathogenesis of GA.The mRNA and protein expression levels of ATGs (ATG3, ATG7, ATG10, ATG5, ATG12, ATG16L1, ATG4B and LC3-2) were measured in peripheral blood mononuclear cells (PBMCs) from 196 subjects, including 57 acute gout patients (AG group), 57 intercritical gout patients (IG group) and 82 healthy control subjects (HC group). The relationship between ATG expression levels and laboratory features was analyzed in GA patients.The expression levels of ATG4B, ATG5, ATG12, ATG16L1, ATG10 and LC3-2 mRNA were much lower in the AG group than in the IG and HC groups (p<0.05), while the ATG7 mRNA level was much higher in the AG group than in the IG and HC groups (p<0.05). The protein expression levels of LC3-2, ATG3, ATG7 and ATG10 were much higher in the AG group than in the other groups, while those of ATG5, ATG12, ATG16L1 and ATG4B were far lower in the AG group than in the other groups (p<0.05). In GA patients, the levels of ATG mRNA and protein correlated with laboratory inflammatory and metabolic indexes.Altered ATG expression suggests that autophagy is involved in the pathogenesis of GA and participates in regulating inflammation and metabolism.[1]Dalbeth N, Choi HK, Joosten LAB, Khanna PP, Matsuo H, Perez-Ruiz F, et al. Gout. Nat Rev Dis Primers. 2019;5: 69.doi:10.1038/s41572-019-0115-y.[2]Schauer C, Janko C, Munoz LE, Zhao Y, Kienhöfer D, Frey B, et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat Med. 2014;20: 511-517.doi:10.1038/nm.3547.[3]Han Y, Zhang L, Xing Y, Zhang L, Chen X, Tang P, et al. Autophagy relieves the function inhibition and apoptosis-promoting effects on osteoblast induced by glucocorticoid. Int J Mol Med. 2018;41: 800-808. doi:10.3892/ijmm.2017.3270.[4]Yang QB, He YL, Zhong XW, Xie WG, Zhou JG. Resveratrol ameliorates gouty inflammation via upregulation of sirtuin 1 to promote autophagy in gout patients. Inflammopharmacology. 2019;27: 47-56.doi:10.1007/s10787-018-00555-4.[5]Mitroulis I, Kambas K, Chrysanthopoulou A, Skendros P, Apostolidou E, Kourtzelis I, et al. Neutrophil extracellular trap formation is associated with IL-1β and autophagy-related signaling in gout. PLoS One. 2011;6: e29318.doi: 10.1371/journal.pone.0029318.[6]Crişan TO, Cleophas MCP, Novakovic B, Erler K, van de Veerdonk FL, Stunnenberg HG, et al. Uric acid priming in human monocytes is driven by the AKT-PRAS40 autophagy pathway. Proc Natl Acad Sci U S A. 2017;114: 5485-5490.doi:10.1073/pnas.1620910114.[7]Lee SS, Lee SW, Oh DH, Kim HS, Chae SC, Kim SK. Genetic analysis for rs2241880(T > C) in ATG16L1 polymorphism for the susceptibility of Gout. J Clin Rheumatol. 2019;25: e113-e115.doi:10.1097/rhu.0000000000000685.Yu-Qin Huang: None declared, Quan-Bo Zhang Grant/research support from: National Natural Science Foundation of China(General Program) (no.81974250) and Science and Technology Plan Project of Sichuan Province (no.2018JY0257), Jian-Xiong Zheng: None declared, gui-lin jian: None declared, tao-hong liu: None declared, Xin He: None declared, fan-ni xiao: None declared, qin xiong: None declared, Yu-Feng Qing Grant/research support from: Science and Technology Project of Nanchong City (no.18SXHZ0522)