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PDGFRα+DPP4+ Fibroblasts-Macrophage Crosstalk Induces Orbital Fibrosis in Treatment-Resistant Thyroid Eye Disease via
Lu Cheng1,2, Jinwei Cheng1,2, Guiling Liang3
1National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
Abstract:
Thyroid eye disease (TED), the leading adult orbital disease, is an autoimmune disorder characterized by fibrosis. Effective anti-fibrotic treatments are scarce, except for orbital decompression surgery involving orbital adipose tissue (OAT) removal, due to high rates of drug resistance following hyperthyroidism treatment and the lack of suitable mouse models. Understanding the mechanisms behind fibrotic remodeling of OAT could aid mouse model development and identify novel therapies. In the present study, stromal vascular fraction cells of OAT from patients with inactive-stage TED, characterized by pronounced fibrosis, are analyzed at single-cell resolution. platelet-derived growth factor receptor (PDGFR)α+dipeptidyl peptidase (DPP)4+ fibroblasts exhibiting progenitor characteristics and fibrotic potential at the transcriptional level are identified. PDGFRα+DPP4+ fibroblasts showed the strongest interactions with macrophages, particularly M2 macrophages, which are enriched and topographically localized within the fibrotic area. Moreover, M2 macrophages promoted extracellular matrix production in PDGFRα+DPP4+ cells via the Growth arrest specific (GAS)6-AXL Receptor Tyrosine Kinase (AXL) signaling pathway. Using a specific AXL inhibitor or AXL knockdown, fibrosis is substantially reduced in PDGFRα+DPP4+ fibroblasts in vitro, and in patient cell-derived orthotopic xenograft models established via GAS6. By identifying pro-fibrotic intercellular networks in OAT, these findings establish a rapid and repeatable mouse model of TED fibrosis and propose the GAS6-AXL axis as a potential therapeutic target for TED.
Insights
Thyroid eye disease (TED) fibrosis involves PDGFRα+DPP4+ fibroblasts interacting with M2 macrophages. Targeting the GAS6-AXL pathway reduces fibrosis, offering a new therapeutic strategy for TED and enabling better mouse models.
Area of Science:
- Ophthalmology
- Immunology
- Cell Biology
Background:
- Thyroid eye disease (TED) is a leading orbital disease characterized by fibrosis, with limited anti-fibrotic treatments.
- Current treatments face drug resistance, and suitable animal models for studying TED fibrosis are lacking.
- Understanding fibrotic remodeling mechanisms in orbital adipose tissue (OAT) is crucial for developing new therapies and models.
Purpose of the Study:
- To investigate the cellular mechanisms driving OAT fibrosis in inactive-stage TED.
- To identify novel therapeutic targets for TED-associated fibrosis.
- To develop a rapid and repeatable mouse model for TED fibrosis.
Main Methods:
- Single-cell analysis of OAT stromal vascular fraction cells from TED patients.
- Identification and characterization of PDGFRα+DPP4+ fibroblasts and their interactions with macrophages.
- Investigating the role of the GAS6-AXL signaling pathway in fibrosis.
- In vitro and in vivo validation using AXL inhibitors and orthotopic xenograft models.
Main Results:
- PDGFRα+DPP4+ fibroblasts with progenitor and fibrotic potential were identified.
- These fibroblasts showed significant interactions with M2 macrophages, which are enriched in fibrotic OAT.
- M2 macrophages promote extracellular matrix production in PDGFRα+DPP4+ cells via the GAS6-AXL pathway.
- AXL inhibition or knockdown significantly reduced fibrosis in vitro and in vivo.
Conclusions:
- Pro-fibrotic intercellular networks involving PDGFRα+DPP4+ fibroblasts and M2 macrophages drive OAT fibrosis in TED.
- The GAS6-AXL signaling pathway is a key mediator of this fibrosis.
- Targeting the GAS6-AXL axis presents a promising therapeutic strategy for TED.
- These findings facilitate the development of a new mouse model for TED fibrosis.
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