Maraviroc attenuates orbital remodeling, inflammation, and lipid dysregulation in a murine model of thyroid eye disease associated with Graves’ disease

TL;DR

Maraviroc reduces inflammation and fat changes in a mouse model of thyroid eye disease without affecting thyroid autoimmunity.

Contribution

Maraviroc, a CCR5 antagonist, is shown to alleviate orbital inflammation and lipid dysregulation in a murine model of thyroid eye disease.

Findings

Maraviroc reduced brown adipose tissue expansion and immune cell infiltration in orbital tissues.

Lipidomic analysis showed reduced triacylglycerols and elevated carnitines, suggesting enhanced fatty acid utilization.

Maraviroc had no significant effect on anti-TSHR antibody levels or hyperthyroidism severity.

Abstract

Graves’ disease (GD) is an autoimmune condition that can extend beyond the thyroid, leading to thyroid eye disease (TED), a disorder marked by orbital inflammation and tissue remodeling.

We explored the therapeutic potential of maraviroc, a CCR5 antagonist, in a mouse model of TED triggered by immunization with the human TSH receptor (hTSHR) A-subunit. Mice received pTriEx1.1neo-hTSHR A-subunit plasmid immunizations, and a subset were treated with maraviroc via drinking water. We assessed thyroid function, orbital tissue changes, immune cell infiltration, and lipid metabolism through serological testing, histology, immunohistochemistry, and untargeted lipidomics.

Maraviroc did not significantly affect anti-TSHR antibody production nor the degree of hyperthyroidism, though it modestly improved thyroid histopathology. Notably, it reduced key signs of orbital disease, including brown adipose tissue expansion, CCL5-positive immune cell infiltration, CD4+ T-cell infiltration and the presence of F4/80+ macrophages. Lipidomic profiling revealed distinct metabolic changes in treated mice, with reduced triacylglycerols and elevated carnitines, indicative of enhanced fatty acid utilization. Composite Z-score analysis reinforced maraviroc’s beneficial effects on orbital inflammation and remodeling.

Maraviroc shows promise as a targeted therapy for TED in the context of GD, offering anti-inflammatory and anti-adipogenic benefits while sparing thyroid autoimmunity. These preclinical findings support further clinical investigation into its role in managing TED.

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