RelA/MicroRNA-30a/NLRP3 signal axis is involved in rheumatoid arthritis via regulating NLRP3 inflammasome in macrophages

Abstract

NLRP3 inflammasome plays an important role in the pathogenesis of rheumatoid arthritis (RA). However, the post-transcriptional regulation of NLRP3 expression by miRNA in synovial macrophages is still not well understood. The aim of the study is to elucidate the mechanisms of RA with the focus on miRNAs mediated post-transcriptional regulation of the NLRP3 inflammasome. Here, we used NLRP3-deficient mice (NLRP3KO) to cross with TNFα-transgenic mice (TNFTG) to generate NLRP3KO/TNFTG mice, and compared their joint phenotypes with those of their TNFTG and wild-type (WT) littermates at 5 months of age. In comparison to WT mice, articular bone volume and cartilage area are decreased, whereas inflammed area, eroded surface, ALP+ osteoblast number, TRAP+ osteoclast number, and the areas of RelA+F4/80+, Caspase-1+F4/80+, IL-1β+F4/80+ synoviocytes are increased in the TNFTG mice. Knockout of NLRP3 ameliorates joint inflammation and bone damage in TNFTG mice. Further, in TNFα-primed BMDMs, RelA positively regulates NLRP3 expression, but negatively regulates miR-30a. Additionally, miR-30a negatively mediates NLRP3 expression by directly binding to its 3ʹ UTR, suggesting a miR-30a-mediated feedforward loop acting on NLRP3. Finally, intra-articular injection of AAV-miR-30a inhibits NLRP3 inflammasome activation, reduces joint inflammation, and attenuates bone damage in TNFTG mice. Thus, RelA/miR-30a/NLRP3 signal axis is involved in RA through regulating NLRP3 Inflammasome in macrophages.

Comprehensive overview of microRNA function in rheumatoid arthritis

“…Subsequently, functional studies further proved that miR-30a directly interacts with the 3’ UTR of NLRP3 and mediates NLRP3 inhibition. 146 …”

Identification of Key Genes and Underlying Mechanisms in Cystic Fibrosis and its Associated Complications Based on Bioinformatics Analysis of Next Generation Sequencing Data Analysis

“…Finally, by constructing miRNA-hub gene regulatory network and TF-hub gene regulatory network, we found that hub genes, miRNAs and TFs might involved in CF and CF associated complications. USF2 [480], RELA [481], STAT1 [482], KLF5 [483] and TP53 [484] were closely related to arthritis. RELA [485] is believed to be related to the occurrence of pancreatitis.…”

Mitochondrial Dysfunction and Oxidative Stress in Rheumatoid Arthritis

“…Moreover, NLRP3-mediated IL-1β secretion could be regulated by a variant within the gene locus encoding PTPN22, which has emerged as an important risk factor for auto-inflammatory disorders, including RA [ 171 ]. In addition to this, polymorphisms and expression of inflammasome genes are associated with susceptibility, disease activity and anti-TNF treatment response in RA [ 172 , 173 , 174 ], while it has also been described how several microRNA (miR-33, miR-20a and miR-30a) act as positive regulator of the NLRP3 inflammasome in RA macrophages [ 175 , 176 , 177 ]. More recently, the synergy of complement C1q with PTX3 in promoting NLRP3 inflammasome over-activation and pyroptosis in RA has been detailed [ 178 ].…”