Thinking inside the box: Current insights into targeting orbital tissue remodeling and inflammation in thyroid eye disease

Abstract

Thyroid eye disease (TED) is an autoimmune disorder that manifests in the orbit. In TED, the connective tissue behind the eye becomes inflamed and remodels with increased fat accumulation and/or increased muscle and scar tissue. As orbital tissue expands, patients develop edema, exophthalmos, diplopia, and optic neuropathy. In severe cases vision loss may occur secondary to corneal scarring from exposure or optic nerve compression. Currently there is no cure for TED, and treatments are limited. A major breakthrough in TED therapy occurred with the FDA approval of teprotumumab, a monoclonal insulin-like growth factor 1 receptor (IGF1R) blocking antibody. Yet, teprotumumab therapy has limitations, including cost, infusion method of drug delivery, variable response, and relapse. We describe approaches to target orbital fibroblasts and the complex pathophysiology that underlies tissue remodeling and inflammation driving TED. Further advances in the elucidation of the mechanisms of TED may lead to prophylaxis based upon early biomarkers as well as lead to more convenient, less expensive therapies.

Keywords: Graves’ orbitopathy; Thyroid eye disease; fibroblast; insulin-like growth factor 1 receptor; microRNA; orbital fibroblast; teprotumumab; therapeutics, targeted therapy.

Figure 1 -

Orbital tissue enlargement and tissue remodeling in thyroid eye disease (TED). Computed tomography (CT) scans of a control, non-TED patient or TED patients that show enlarged orbital tissue with mostly fat (type I) or mostly scar/muscle (type II). Both type I and type II patient CT scans reveal increased orbital volume and proptosis compared to the control, non-TED patient in the image on the left. The orbital space is largely filled with less dense fat tissue in type I patients (as shown in the middle CT scan). In type II TED patients, dense muscle/scar tissue is readily observed by CT scan (as shown in the image on the right). Control and Type II images from Radiopaedia.org (rID 44049 and 9365). Type I image reprinted with permission from Hudson et al.

Figure 2 -

Cellular mediators of thyroid eye disease pathology. Many different cell types play important roles in driving inflammation and tissue remodeling observed in TED. Circulating B cells, T cells, macrophages, mast cells and fibrocytes can traffic to the orbit and produce many different inflammatory mediators including cytokines such as IL-1β, IL-6 and TGFβ and lipid mediators such 15d-PGJ₂ and PGE₂. Autoantibodies against the TSHR, the main autoantigen in TED, also accumulate in the orbit due to the presence of TSHR expressing orbital fibroblasts. These cells and inflammatory mediators lead to a microenvironment of sustained activation of orbital fibroblasts that can: 1) differentiate into fat storing adipocytes through adipogenesis, 2) secrete excessive extracellular matrix molecules including collagen and hyaluronan, 3) proliferate and turn into scar-forming myofibroblasts, and 4) secrete additional cytokines and mediators such as IL-6, IL-8 and PGE₂ that promote continued inflammation and tissue remodeling seen in TED pathology. Image created with BioRender.com.

Figure 3 -

Molecular pathways controlling fibroblast activation in thyroid eye disease. Multiple intracellular pathways mediate sustained activation of orbital fibroblasts in TED. Surface receptors present on orbital fibroblasts transmit extracellular signals by inducing protein cascades, often mediated by increased cyclic AMP (cAMP), phosphatidyl inositol (PI3K) or protein phosphorylation (P). These activated pathways ultimately lead to tissue remodeling and TED pathology. Autoantibodies bind to the TSHR, a G-protein coupled receptor that activates PI3K and cAMP cascades. Some autoantibodies may also bind and activate the IGF1R, a receptor tyrosine kinase that also induces PI3K and Ras signaling. There is also evidence that IGF1R and TSHR receptors co-localize and interact on orbital fibroblasts to further increase TSHR-IGF1R signaling. Orbital fibroblasts express IL-6 and IL-1β receptors that, when bound by cognate inflammatory cytokines, activate STAT3, JNK and AP-1 signaling pathways. Active TGFβ binds to TGFβ receptors on the surface of fibroblasts to turn on Smad transcription factors and induce MAPK/p38 signaling. Frizzled receptors that mediate Wnt/GSK-3β/β-catenin signaling are also expressed on orbital fibroblasts. Wnt pathways are blocked during adipogenic stimulation but are activated to induce proliferation, myofibroblast and extracellular matrix production. While these receptors mediate signals through their respective extracellular ligands/activators, many of the downstream signaling pathways interact and lead to further activation of orbital fibroblasts. Depending on these downstream interactions and complex interplay of extracellular mediators, the pathways can drive adipogenesis, cellular proliferation, extracellular matrix production, myofibroblast formation, and inflammatory cytokine production.