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

Qiudong Yang,Jiali Shi,Yuyi Chen,Hua Yuan,Wen Sun,Wenhua Zhao,Ran Qin,Yue Chen,Hua Wang,Ruixia Wang

doi:10.1038/s41419-021-04349-5

Qiudong Yang, Jiali Shi + Show 8 more

Open Access

https://doi.org/10.1038/s41419-021-04349-5

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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.

Highlights

Rheumatoid arthritis (RA) is a chronic, destructive autoimmune inflammatory disorder, affecting 0.5–1% of the population worldwide [1]
The data revealed that the areas of F4/80+ macrophages and RelA+ synoviocytes were significantly increased in TNFTG mice and NLRP3KO/TNFTG mice compared with those of the WT
Since NLRP3 gene expression can be governed by miRNAs via post-transcriptional regulation, we investigated the expression of miRNAs in ankle joints of TNFTG mice and their WT littermates by qPCR with the focus on highly conserved monocyte/macrophagespecific miRNAs [26]

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic, destructive autoimmune inflammatory disorder, affecting 0.5–1% of the population worldwide [1]. It is one of the most common forms of arthritis which causes synovitis, bone erosion and joint deformity [2]. Many studies have shown a large number of pro-inflammatory cytokines are active in the joints of patients with RA [3, 4] Among these cytokines, TNFα has gained much attention because of its position at the apex of the pro-inflammatory cytokine cascade, and its dominance in the pathogenesis of RA [5]. The mechanisms underlying the progression of RA remain largely unknown

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