Elevated Fcy receptor expression augments pro-inflammatory macrophage phagocytosis in systemic sclerosis and associated rheumatic diseases

Objectives: To investigate the pro-phagocytic phenotype of macrophages in SSc and other rheumatic diseases by examining their activation, signaling pathways, and treatment responses, with the goal of uncovering mechanisms that drive enhanced phagocytosis.

Methods: Single-cell RNA sequencing (scRNA-seq) datasets (GSE138669/GSE212109) from skin and lung macrophages of healthy controls and SSc patients were analyzed. Human monocyte-derived macrophages (hMDM) were differentiated from CD14+ monocytes from healthy controls, SSc, RA, PsA, and axSpA patients. In selected experiments, hMDMs were pretreated with 0.1 μM nintedanib. Phagocytic activity was quantified using pHrodo bioparticles and flow cytometry. Macrophage surface markers were evaluated by flow cytometry, NF-κB signaling by Western blot, and gene expression by RT-qPCR.

Results: Analysis of scRNA-seq datasets revealed a pro-phagocytic signature in SSc-affected organs. SSc macrophages, particularly the FCGR3A hi cluster in skin, exhibited elevated expression of FCGR genes and enriched FcγR-mediated phagocytosis pathways, accompanied by pro-inflammatory markers. This phenotype extended to FCN1 hi lung macrophages in SSc patients with interstitial lung disease, indicating a systemic pro-inflammatory and phagocytic profile. hMDMs from SSc, RA, and PsA patients demonstrated enhanced phagocytic activity in vitro. Elevated FcγRI and FcγRII levels were identified as key drivers of increased phagocytic activity and subsequent IL-6-driven inflammation. Nintedanib showed reduction in FcγRI expression, suggesting its potential therapeutic benefit in attenuating the phagocytic process.

Conclusion: This study highlights FcγR-expressing macrophages as drivers of phagocytosis and inflammatory responses in SSc. Dysregulated activation of these macrophages could lead to persistent inflammation and fibrosis in rheumatic diseases, highlighting new potential therapeutic approaches.