Batal, A.; Pamnani, S.; Zhou, S.; Bou-Gharios, G.; Philip, A.

Fibroproliferative diseases such as systemic sclerosis are complex conditions characterized by chronic skin inflammation and progressive fibrosis, with fibroblast activation as a central feature. While Transforming Growth Factor Beta (TGF-{beta}) signaling is a well-established driver of fibrosis in SSc, inflammatory pathways such as Nuclear Factor Kappa B (NF-{kappa}B) also contribute substantially to disease morbidity. We previously identified CD109 as a TGF-{beta} co-receptor and negative regulator of fibrotic signaling; however, its role in inflammatory signaling remains unknown. Here, we investigate the function of CD109 in regulating inflammatory signaling in skin fibroblasts. We show that, CD109 co-localizes and associates with Toll-like receptors (TLR2, TLR4) and tumor necrosis factor receptors (TNFRI, TNFRII), and that loss of CD109 enhances TNF--induced NF-{kappa}B activation and reprograms cytokine production in human dermal fibroblasts. Furthermore, both global and fibroblast-specific CD109 knockout mice exhibit increased immune cell infiltration and skin inflammation. In parallel, single-cell transcriptomic analyses across a pan-disease fibroblast atlas show that CD109 expression is preferentially maintained in structural and homeostatic fibroblast subtypes, whereas immune-interacting fibroblast subsets consistently display decreased CD109 levels. Pathway-level analyses of fibroblast pseudobulk samples reveal altered activity of canonical inflammatory pathways in SSc compared to healthy skin. Together, these findings identify CD109 as a fibroblast-intrinsic negative regulator of inflammatory signaling and suggest a broader role for CD109 in modulating inflammatory responses in systemic sclerosis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/736423v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): [email protected]@118c791org.highwire.dtl.DTLVardef@1d63057org.highwire.dtl.DTLVardef@ffa2bf_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract: CD109 Restrains Fibroblast-Driven Inflammation by Modulating NF-{kappa}B Signaling. Generated using FigureLabs.ai and edited using Adobe Photoshop. C_FIG