Macrophage plasticity in thyroid eye disease: dual effects of inflammation and fibrosis

Thyroid Eye Disease (TED), also known as Graves' ophthalmopathy, is an organ-specific inflammatory disorder associated with autoimmune thyroid dysfunction. Its primary pathological features include immune cell infiltration of orbital tissues, fat hyperplasia, and fibrotic remodeling. The pathogenesis centers on abnormal expression of TSHR on orbital fibroblasts and immune attacks mediated by autoantibodies. Recent studies increasingly reveal that infiltrating immune cells, particularly highly plastic macrophages, do not simply divide into static M1/M2 phenotypes. Instead, they exist within a functional continuum precisely regulated by transcriptional and epigenetic mechanisms, dynamically adjusting their functional states in response to microenvironmental signals. Along this continuum, macrophages in early disease stages lean toward the pro-inflammatory pole. Activation of transcription pathways like NF-κB, coupled with concomitant epigenetic remodeling, drives the release of inflammatory mediators such as IL-6 and TNF-α, thereby initiating and amplifying inflammatory cascades. During disease progression, macrophages shift toward the pro-fibrotic end. Their functional state is influenced by the sustained activation of transcriptional programs like TGF-β/Smad and STAT3, as well as the consolidation effects of epigenetic mechanisms such as DNA methylation and histone modifications. This facilitates pathological tissue repair and fibrosis through signaling pathways including GAS6-AXL and PDGF. This review systematically examines the dynamic regulatory role of macrophages in TED, delves into their complex interaction networks with fibroblasts, adipocytes, and lymphocytes. It further envisions novel therapeutic strategies targeting the macrophage functional continuum and its underlying transcriptional and epigenetic regulatory mechanisms. This aims to establish a pathological framework for TED centered on the spatiotemporal evolution of macrophages, providing theoretical foundations and translational perspectives for developing temporal and precision therapies that transcend conventional immunosuppression.