HDAC2 exacerbates rheumatoid arthritis progression via the IL‐17‐CCL7 signaling pathway

Abstract

Histone deacetylases (HDACs) have been reported to regulate the immune response in rheumatoid arthritis (RA). The current study aimed to explore key HDACs and their molecular mechanism in RA. First, the expression of HDAC1, HDAC2, HDAC3 and HDAC8 in RA synovial tissue was determined by qRT‐PCR. The effects of HDAC2 on the proliferation, migration, invasion, and apoptosis of fibroblast‐like synoviocytes (FLS) in vitro were studied. Furthermore, collagen‐induced arthritis (CIA) rat models were established to evaluate the severity of arthritis in joints, and the levels of inflammatory factors were examined by immunohistochemistry staining, ELISA, and qRT‐PCR. Transcriptome sequencing was used to screen differentially expressed genes (DEGs) with HDAC2 silencing in the synovial tissue of CIA rat, and downstream signaling pathways were predicted by enrichment analysis. The results showed that HDAC2 was highly expressed in the synovial tissue of RA patients and CIA rats. Overexpressed HDAC2 promoted FLS proliferation, migration, and invasion and inhibited FLS apoptosis in vitro, resulting in secretion of inflammatory factors and RA exacerbation in vivo. There were 176 DEGs, including 57 downregulated and 119 upregulated genes, after silencing HDAC2 in CIA rats. DEGs were primarily enriched in Platinum drug resistance, IL‐17 as well as the PI3K‐Akt signaling pathways. CCL7, which was implicated in the IL‐17 signaling pathway, was downregulated after HDAC2 silencing. Furthermore, CCL7 overexpression aggravated the development of RA, which was demonstrated to be effectively attenuated by HDAC2 suppression. In conclusion, this study demonstrated that HDAC2 exacerbated the progression of RA by regulating the IL‐17‐CCL7 signaling pathway, suggesting that HDAC2 may be a promising therapeutic target for RA treatment.

Inhibition of IL-17 signaling in macrophages underlies the anti-arthritic effects of halofuginone hydrobromide: Network pharmacology, molecular docking, and experimental validation

“…3 B, Table S4 ). Notably, among these pathways, the top-ranked in relation to RA was the IL-17 signaling pathway, which has been reported to aggravate RA when activated [ 26 ]. This process involves the expression of IL-17, NF-κB, and MMP [ 27 , 28 ].…”

Associations of the circulating levels of cytokines with risk of ankylosing spondylitis: a Mendelian randomization study

“…Previously, only one case-control study was found to observe significantly elevated MCP-3/CCL7 levels in the serum of AS patients ( 46 ), but further studies between the two were lacking.MCP-3/CCL7 is a chemokine that attracts monocytes during inflammation and metastasis. MCP-3/CCL7 was found to be involved in the IL-17 signaling pathway, and overexpression of MCP-3/CCL7 exacerbates the progression of RA ( 47 ). Therefore, inhibition of the IL-17-CCL7 signaling pathway may be a promising therapeutic target for RA.…”

Postbiotics in rheumatoid arthritis: emerging mechanisms and intervention perspectives

“…Notably, those inhibitory effects of SCFAs on HDAC activity is not limited to immune cells in the intestine, but also extends to other tissues and organs through the circulation. The inhibition of HDACs leads to the inactivation of NF-κB, which subsequently reduces the release of inflammatory cytokines in RA patients and arthritic mice (Kim et al, 2018;Mao et al, 2023;Vijaykrishnaraj et al, 2023).…”