Targeting LRRC15+ Pathological Fibroblasts in Autoimmune Inflammation 9009

Abstract Description Inflammation is a hallmark of autoimmune diseases resulting from aberrant activity of immune and stromal cells. Particularly, fibroblasts release chemokines and cytokines to recruit immune cells driving inflammation. Targeting these inflammatory fibroblasts presents a potential avenue for developing novel therapeutics to alleviate autoimmunity and fibrosis. Leucine rich repeat containing 15 (LRRC15), a single pass type I membrane protein, is significantly upregulated on inflammatory fibroblast subsets in patients and animal models of autoimmune diseases. LRRC15 facilitates binding to collagen and is upregulated in the presence of TGFβ, a key regulator of fibrosis. To explore the function of LRRC15, knockdown of LRRC15 resulted in a significant reduction in chemokine secretion following TNFα stimulation, suggesting a role of LRRC15 in inducing inflammation. Transcriptomic analyses revealed a substantial increase in Lrrc15 expression in fibroblasts in Rheumatoid Arthritis (RA) synovium and Systemic Sclerosis (SSc) skin biopsies when compared to healthy controls. Additionally, spatial transcriptomics highlighted the clustering of LRRC15+ cells within tertiary lymphoid structures in RA synovial samples. We also observed the upregulation of LRRC15 in mouse models of wound healing and bleomycin-induced fibrosis. Thus, removal of LRRC15-expressing fibroblasts could provide a new therapeutical opportunity to reduce tissue inflammation in RA, SSc, and other autoimmune disorders. Funding Sources Merck Topic Categories Therapeutic Approaches to Autoimmunity (THER)