Canonical fibrotic activation of fibroblast by dysfunctional scar associated macrophages in lupus nephritis 4579

Abstract Description Organ damage in lupus nephritis (LN) involves immune cell-fibroblast interactions. Previously, we identified renal disease-associated infiltrating Classical 2 (C2) and resident macrophages (RMs), which correlate with higher LN activity and chronicity scores. Both acquire a Scar-Associated Macrophage (SAM) gene signature (CTSB, SPP1, FABP5, TREM2, CD63) despite differing origins, and their impacts on fibroblasts remain unclear. We examined the phagocytic capacity and influence of these macrophage subsets on fibroblasts. Using lupus mouse models, macrophages and fibroblasts were isolated and characterized via single-cell and spatial genomics, mapping SAM and fibroblast gene signatures. Flow cytometry revealed higher frequencies of CD9+ TREM2+ SAMs in nephritic kidneys, which co-localized with aSMA+ fibroblasts. RMs in nephritic kidneys exhibited impaired phagocytosis of immune complexes and apoptotic cells, contrasting with preserved uptake of latex beads. Nephritic RMs enhanced fibroblast size and induced an activated FAP+ phenotype compared to pre-nephritic counterparts. To model C2-fibroblast interactions, bone marrow-derived macrophages were polarized into induced SAMs (iSAMs) using GM-CSF and IL-17A. iSAM-fibroblast cocultures enhanced fibroblast migration and wound repair while inducing a collagen-driven tissue remodeling signature with activation of YAP/TAZ and WNT pathways. These findings suggest that profibrotic SAM-fibroblast interactions drive LN pathology. Funding Sources NIH T32AI155392-01 NIH RO1DK131482-01 DOD LR200070 Topic Categories Basic Autoimmunity (BA)