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Hypermethylation Of NLRP3 Promoter Region Could Be Responsible For Decreased Gene Expression, Inflammasome Malfunction And Gut Dysbiosis In Early Phase Juvenile Spondyloarthritis

Juvenile spondyloarthritis (jSpA) is a complex disease with both genetic and environmental factors contributing to the etiology. Recently obtained gene signatures in jSpA patients revealed TLR4 and CXCR4 gene had increased, while NLRP3 and PTPN12 had decreased expression, though the mechanism(s) responsible for those alterations remained unknown. Since it is well known that epigenetic mechanisms control gene expression and are influenced by external stimuli linking environment and gene function, the aim of the present study was to investigate the possible mechanistic role of DNA promoter region methylation and several non-coding microRNAs (miR- 150, miR-146a, miR-181a, miR-223) in jSpA patients related to the expression of genes with observed alterations (TLR4, CXCR4, NLRP3 and PTPN12). For that purpose, peripheral blood samples were obtained from 19 patients diagnosed with jSpA according to ILAR classification criteria for enthesitis related arthritis (ErA) and seven gender and age matched subjects without diagnosis of inflammatory disease. Methylated DNA Immunoprecipitation (MeDIP) analysis revealed significant hypermethylation of NLRP3 gene promotor while expression analysis of selected microRNAs showed no significant difference in fold change between two groups of participants. Our study therefore indicated epigenetic modifications are probably responsible for some of the expression alterations in jSpA patients in the initial phase of the disease. Since NLRP3 has a crucial role in inflammasome assembly and infllammasomes have been shown to shape microbiota, it is reasonable to assume that dysbiosis in jSpA patients can at least partially be explained by reduced NLRP3 expression due to hypermethylation, stressing for the first time the epigenetic contribution to jSpA pathophysiology. While it is still not clear if these epigenetic alterations are caused by genetic mutations in epigenetic factors or exposure to certain environmental factors that mediate the occurrence of aberrant epigenetic profiles, the possibility of reverting epigenetic modifications opens up whole new prospects for therapeutic treatment of these intricate disease.

juvenile spondyloarthritis ; epigenetics ; jSpA ; microRNAs ; methylation ;

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