Lakhanpal, A. | Search bioRxiv

bioRxiv2026

SPP1hi macrophages in fibrin niches promote hyperplastic tissue remodeling in rheumatoid arthritis synovium

In chronic inflammatory diseases, maladaptive tissue remodelling is driven by a complex interplay of resident cells, immune filtrates and the extracellular matrix. In the autoimmune disorder rheumatoid arthritis (RA), synovial tissue undergoes assive expansion to form an invasive pannus that drives the erosion of cartilage and bone. The mechanisms mediating this ggressive growth are incompletely defined. Using spatial transcriptomics profiling of patient tissue, we detected an bundance of proliferating fibroblasts near the synovial tissue lining surface and adjacent to SPP1hi macrophages. Notably, ese synovial lining regions were also distinctly marked by deposits of the clot-forming protein fibrin. While the SPP1hi acrophages phenotypically resemble pro-fibrotic macrophages that drive lung and liver fibrosis, these niches were devoid f the dense highly ordered collagen that marks fibrosis. Functionally, we found that SPP1hi macrophages degrade and hagocytose fibrin matrices and promote fibroblast proliferation. As fibrin provides transient matrices for de novo tissue eneration in the context of wound healing, these data support a model of hyperplastic tissue outgrowth involving SPP1hi acrophages, fibroblasts and fibrin matrices adhered to the exterior synovial tissue surface. While current RA therapies rimarily aim to dampen pro-inflammatory responses, our findings provide rationale for targeting pro-generative pathways nd SPP1hi macrophages. Once Sentence SummarySPP1hi macrophages in RA synovial fibrin deposits promote tissue hyperplasia.

immunology↗

bioRxiv2025

Sexual dimorphism in zymosan-induced arthritis is linked with a higher IFN response in myeloid cell subsets that faithfully recapitulate RA synovial cell clusters

A key feature of rheumatoid arthritis (RA) is sexual dimorphism, with a higher incidence of RA in females. Myeloid cells are key drivers of the inflammatory effector phase of RA, but little is known about their contribution to a sexually dimorphic arthritis phenotype. We wished to utilize an arthritis model that recapitulates RA pathogenic myeloid cell subsets defined by single cell transcriptome analysis to investigate sex differences in human disease-relevant cell types and related molecular pathways. We developed a computational strategy that rigorously maps scRNAseq-defined mouse arthritis myeloid cells and clusters onto previously defined RA subsets. Synovial myeloid cells in the zymosan-induced arthritis (ZIA) model closely recapitulated four pathogenic RA myeloid cell subsets, strongly supporting the disease-relevance of the ZIA model. ZIA also effectively modeled myeloid cells in immune checkpoint inhibitor arthritis (ICI-A). These RA, ICI-A and ZIA myeloid cells express genes in TNF-NF-kB, PGE2, and IFN-STAT pathways. In ZIA, an induction phase dominated by cell clusters expressing NF-kB and PGE2 pathways transitioned to peak arthritis characterized by cell subsets co-expressing NF-kB and IFN pathways, as occurs in RA and various inflammatory diseases. Female mice exhibited increased arthritis linked with early induction of interferon-stimulated genes and increased expansion of IFN signature-expressing cell subsets. Our study identifies a computational strategy and animal model that enables investigation of recently described pathogenic myeloid cell subsets, and links increased arthritis in female mice with specific myeloid cell subsets that exhibit a stronger IFN response.

immunology↗