PLCL1 regulates fibroblast-like synoviocytes inflammation via NLRP3 inflammasomes in rheumatoid arthritis

Abstract

Background Phospholipase C-like 1 (PLCL1), a protein that lacks catalytic activity, has similar structures to the PLC family. The aim of this research was to find the function and underlying mechanisms of PLCL1 in fibroblast-like synoviocyte (FLS) of rheumatoid arthritis (RA). Methods In this study, we first analyzed the expression of PLCL1 in the synovial tissue of RA patients and K/BxN mice by immunohistochemical staining. Then silencing or overexpressing PLCL1 in FLS before stimulating by TNF-α. The levels of IL-6, IL-1β and CXCL8 in FLS and supernatants were detected by Western Blot (WB), Real-Time Quantitative PCR and Enzyme Linked Immunosorbent Assay. We used INF39 to specifically inhibit the activation of NLRP3 inflammasomes, and detected the expression of NLRP3, Cleaved Caspase-1, IL-6 and IL-1β in FLS by WB. Result When PLCL1 was silenced, the level of IL-6, IL-1β and CXCL8 were down-regulated. When PLCL1 was overexpressed, the level of IL-6, IL-1β and CXCL8 were unregulated. The previous results demonstrated that the mechanism of PLCL1 regulating inflammation in FLS was related to NLRP3 inflammasomes. INF39 could counteract the release of inflammatory cytokines caused by overexpression of PLCL1. Conclusion Result showed that the function of PLCL1 in RA FLS might be related to the NLRP3 inflammasomes. We finally confirmed our hypothesis with the NLRP3 inhibitor INF39. Our results suggested that PLCL1 might promote the inflammatory response of RA FLS by regulating the NLRP3 inflammasomes.

A genome-wide association study suggests new susceptibility loci for primary antiphospholipid syndrome

“…ESR2 (estrogen receptor 2) (rs932657402, p-value=1.13×10 − 6 , OR [95% CI]=0.13 [0.06-0.30]) and HGF (hepatocyte growth factor) (rs75427037, p-value=1.57 x 10 −6 , OR [95% CI]=0.23 [0.12-0.42]), have been associated with thrombotic events [31, 32], while EPHA7 (rs117489460, p-value=4.50 x 10 −6 , OR [95% CI]=0.19 [0.09-0.38]) is expressed in vascular endothelial cells and shows higher expression levels during inflammation [33]. Other suggestive loci identified in our meta-analysis have been previously associated with other immune-mediated diseases, such as WNT11 (Wnt family member 11) and DLG2 (discs large MAGUK scaffold protein 2) with inflammatory bowel disease, ANKRD50 (ankyrin repeat domain containing 50) with systemic lupus erythematosus, and PLCL1 (phospholipase C like 1) gene expression with rheumatoid arthritis [34–37].…”

multi-GPA-Tree: Statistical approach for pleiotropy informed and functional annotation tree guided prioritization of GWAS results

“…The PLCL1 gene in chromosome 2, IL2RA gene in chromosome 10 and UHRF1BP1 gene in chromosome 6 had the most number of protein-coding SNPs with 5 SNPs related to coding the PLCL1 gene and 4 SNPs each related to coding the IL2RA and UHRF1BP1 genes. The PLCL1 gene is known to promote inflammatory response by regulating the NLRP3 inflammasomes, a component of the immune system related to activation and secretion of proinflammatory cytokines [ 30 ]. Similarly, IL2RA gene expression has been reported on activated T and B cells, regulatory T cells, activated monocytes, and natural killer cells [ 31 , 32 ], and the UHRF1BP1 gene plays a role in non-conservative amino-acid change and is related to RNA processing complex that is targeted by SLE autoantibodies [ 33 ].…”