Targeting LRRC15-expressing fibroblasts holds therapeutic potential to ameliorate inflammation and fibrosis in autoimmune diseases

OBJECTIVES: Targeting stromal cells such as inflammatory fibroblasts presents a potential avenue to alleviate autoimmune inflammation and fibrosis. This study aimed to characterize LRRC15 expression in rheumatoid arthritis (RA) and systemic sclerosis (SSc) across fibroblast subsets and assess whether targeting LRRC15-expressing fibroblasts can be beneficial for the treatment of fibrosis and fibroblast-mediated inflammation. METHODS: We conducted transcriptomic analyses of Lrrc15 in bulk and single-cell RNA-seq datasets from RA and SSc. We used flow cytometry, RNA-seq, immunohistochemistry and spatial transcriptomics to define Lrrc15 expression patterns in diseased tissues. We performed in vitro and in vivo assays to elucidate the function of LRRC15 in inflammatory fibroblasts. RESULTS: When compared with healthy controls, we observed a higher activated fibroblast gene signature in RA synovium and SSc skin biopsies that correlated with Lrrc15 expression. Multi-IF imaging highlighted the clustering of LRRC15-expressing fibroblasts within tertiary lymphoid structures (TLS) in RA synovium. Knockdown of Lrrc15 in primary cells reduced production of TNF-α induced inflammatory chemokines including CCL3 and CXCL10. We confirmed LRRC15 upregulation in mouse models of wound healing and pulmonary fibrosis. Inflammatory fibroblasts with high LRRC15 expression were susceptible to NK cell-mediated LRRC15 specific lysis in vitro. CONCLUSION: Targeting LRRC15+ fibroblasts and fibrotic microenvironment may offer a new therapeutic opportunity to reduce inflammation in RA, SSc and other autoimmune disorders where activated fibroblasts play a role in disease pathogenesis.