Brevilin A, a novel LRRC15 inhibitor, exerts potent anti-rheumatoid arthritis effects by inhibiting the LRRC15/STAT3 signaling pathway

Abstract

Leucine-rich repeat-containing 15 (LRRC15) is a transmembrane protein that is highly expressed in the synovium of patients with rheumatoid arthritis (RA). Brevilin A (BrA), an active compound isolated from Centipeda minima, exerts potent anti-inflammatory effects. However, the anti-RA effect of BrA and its underlying mechanism of action of BrA have not been fully elucidated. Transcriptome analysis was performed to explore biomarkers of RA. An lipopolysaccharide (LPS)-induced RAW264.7 macrophage model, a TNF-α-stimulated RA fibroblast-like synoviocytes (RA-FLSs) model, as well as a collagen-induced arthritis (CIA) rat model were used to explore the anti-RA effects of BrA. Moreover, inhibition or overexpression of LRRC15 was performed to explore the role of LRRC15 signaling in the anti-RA effects of BrA. Transcriptome analysis of patients with RA revealed that LRRC15 expression was significantly upregulated in the synovial tissue of RA patients. BrA significantly downregulated the expression of inflammation-related markers in cell models, and inhibited their proliferation and migration; Moreover, it significantly reduced joint swelling and cartilage damage in CIA rats. Further mechanistic studies suggest that inhibition of LRRC15 inhibits cell proliferation and migration; and overexpression of LRRC15 increases the protein levels of STAT3’s downstream metastasis-related markers. Our findings suggest that BrA, a novel LRRC15 inhibitor, has promising anti-RA activity and potently inhibits LRRC15/STAT3 signaling pathway both in vivo and in vitro. This study not only supports the development of BrA as a novel therapeutic agent for RA treatment, but also paves the way for the development of other LRRC15-targeting therapeutic strategies.