Teprotumumab Divergently Alters Fibrocyte Gene Expression: Implications for Thyroid-associated Ophthalmopathy

Author:

Fernando Roshini12,Smith Terry J12ORCID

Affiliation:

1. Department of Ophthalmology and Visual Sciences, Kellogg Eye Center , Ann Arbor, MI 48105 , USA

2. Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School , Ann Arbor, MI 48105 , USA

Abstract

Abstract Context Teprotumumab, an IGF-I receptor (IGF-IR) inhibitor, is effective in thyroid-associated ophthalmopathy (TAO). The drug can modulate induction by TSH of IL-6 and IL-8 in CD34+ fibrocytes and their putative derivatives, CD34+ orbital fibroblasts (CD34+ OF). Fibrocytes express multiple thyroid autoantigens and cytokines implicated in TAO, which are downregulated by Slit2. Inflammation and disordered hyaluronan (HA) accumulation occur in TAO. Whether teprotumumab alters these processes directly in fibrocytes/CD34+ OF remains uncertain. Objective Determine teprotumumab effects on expression/synthesis of several TAO-relevant molecules in fibrocytes and GD-OF. Design/Setting/Participants Patients with TAO and healthy donors were recruited from an academic endocrine and oculoplastic practice. Main outcome measures Real-time PCR, specific immunoassays. Results Teprotumumab attenuates basal and TSH-inducible autoimmune regulator protein, thyroglobulin, sodium iodide symporter, thyroperoxidase, IL-10, and B-cell activating factor levels in fibrocytes. It downregulates IL-23p19 expression/induction while enhancing IL-12p35, intracellular and secreted IL-1 receptor antagonists, and Slit2. These effects are mirrored by linsitinib. HA production is marginally enhanced by teprotumumab, the consequence of enhanced HAS2 expression. Conclusion Teprotumumab affects specific gene expression in fibrocytes and GD-OF in a target-specific, nonmonolithic manner, whereas IGF-IR control of these cells appears complex. The current results suggest that the drug may act on cytokine expression and HA production systemically and locally, within the TAO orbit. These findings extend our insights into the mechanisms through which IGF-IR inhibition might elicit clinical responses in TAO, including a potential role of Slit2 in attenuating inflammation and tissue remodeling.

Funder

NIH

Autoimmune Center of Excellence

NEI Core

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

Cited by 3 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. TSHR-IGF-IR complex drives orbital fibroblast misbehavior in thyroid eye disease;Current Opinion in Endocrinology, Diabetes & Obesity;2024-07-31

2. Outcomes of Strabismus Surgery Following Teprotumumab Therapy;American Journal of Ophthalmology;2024-06

3. Fibrocyte Participation in Thyroid-Associated Ophthalmopathy Suggests New Approaches to Therapy;Ophthalmic Plastic & Reconstructive Surgery;2023-12

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