RESEARCHERS unveiled a groundbreaking study shedding light on the complex molecular interplay driving fibrosis in diffuse systemic sclerosis (dcSSc) at ACR 2024 in Washington, D.C., USA. Using cutting-edge multiomic and spatial transcriptomic technologies, the study highlights pivotal signaling interactions between macrophages and fibroblasts, uncovering potential therapeutic targets for this challenging autoimmune disease.
The study group from Dartmouth College, Lebanon, New Hampshire, USA, collected skin biopsies from 10 treatment-naïve patients with early-stage dcSSc, alongside four healthy controls, and conducted bulk RNA-seq, single nuclei multiome, and spatial transcriptomic analyses. Their findings revealed a critical role for the PI3K-AKT-mTOR pathway, activated by platelet-derived growth factor (PDGF) secreted by macrophages and other innate immune cells. Fibroblasts in SSc skin showed heightened expression of PI3K pathway-associated transcription factors, driving inflammatory and fibrotic responses.
Spatial transcriptomics further highlighted increased PDGF secretion by innate immune cells, matching the increased expression of PDGFR in fibroblasts. The research shows unique insights into the molecular interactions between cell types in early, untreated SSc skin, identifying hallmarks of SSc skin fibrosis. Inhibiting PI3K to reduce tissue thickness lays the groundwork for a potential therapeutic target for disrupting the immune-fibrosis axis in SSc skin.
Reference: Jarnagin H et al. Single Nuclei Multiome and Spatial Transcriptomic Analysis of Early, Untreated SSc Skin Identifies Signaling Interactions Between Macrophages and Fibroblasts. Abstract 1643. ACR Convergence 2024, November 16-19, 2024.
