Inflammation Reprograms Fibro-Adipogenic Progenitors (FAPs) to Form Immunopathogenic Niches in Myositis

Despite immunosuppressive treatments, Idiopathic inflammatory myopathies (IIMs) are characterized by persistent muscle inflammation and fibrosis, with mechanisms of disease perpetuation remaining unclear. Current therapies often fall short, highlighting a critical gap in understanding the cellular drivers of chronic disease activity. Tissue-resident stromal cells, specifically fibro-adipogenic progenitors (FAPs), are known for their role in muscle repair but their contribution to chronic inflammation in IIMs has been largely unrecognized. This study investigates how FAPs adapt to inflammatory microenvironments and sustain immunopathogenic niches, potentially offering novel therapeutic targets beyond traditional immunosuppression.

Researchers investigated the role of FAPs in myositis using single-nucleus and spatial transcriptomics on muscle biopsies from 24 IIM patients and 6 non-diseased controls. They characterized FAP adaptation to different immune environments (T-cell vs. macrophage-centric). To elucidate mechanistic drivers, primary human FAPs were exposed to TGF-β and EGF to observe changes in differentiation and gene accessibility. Ligand-receptor analyses and trajectory modeling were employed to identify key signaling pathways and transcription factors involved in FAP reprogramming.

FAPs demonstrated remarkable plasticity, adapting their gene expression programs to their local tissue context, favoring T-cell-centric programs in T-cell-rich environments and myeloid programs in macrophage-rich areas. Spatially, FAPs formed inflammatory niches by co-localizing with muscle stem cells and activated macrophages, facilitating crucial cell-to-cell communication. > A dual-input mechanism was identified where infiltrating immune cells (via TGF-β) and myofibers (via EGF) converge on the AP-1 transcription factor, driving FAP differentiation towards a pro-inflammatory and pro-fibrotic phenotype. Mechanistically, exposure of primary human FAPs to TGF-β and EGF induced a primed state by altering the accessibility to AP-1 regulatory elements, suggesting a direct role in transcriptional reprogramming. These findings reveal a previously unrecognized role of FAPs in sustaining IIM pathology.