Macrophage-Orbital Fibroblast Interaction and Hypoxia Promote Inflammation and Adipogenesis in Graves’ Orbitopathy

Görtz, Gina-Eva; Philipp, Svenja; Bruderek, Kirsten; Jesenek, Christoph; Horstmann, Mareike; Henning, Yoshiyuki; Oeverhaus, Michael; Daser, Anke; Bechrakis, Nikolaos E.; Eckstein, Anja; Brandau, Sven; Berchner‐Pfannschmidt, Utta

doi:10.1210/endocr/bqac203

Cited by 10 publications

(12 citation statements)

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“…In our analysis we confirmed the significant association of smoking with a more severe course of GO as reported before in clinical and experimental studies ( 23 , 29 – 31 , 42 ). As in a recent EUGOGO report about a quarter of patients were current smokers (24.2% vs 28% here) ( 35 ).…”

Section: Discussionsupporting

confidence: 91%

Influence of biological sex, age and smoking on Graves’ orbitopathy – a ten-year tertiary referral center analysis

et al. 2023

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PurposeSeverity of Graves’ orbitopathy (GO) shows wide individual differences. For optimal treatment, it is important to be able to predict the natural course of the disease as accurate as possible to counteract with anti-inflammatory and surgical treatment. Therefore, we aimed to further elucidate the impact of sex, age and smoking on GO.MethodsWe collected the clinical and demographic data of all patients of our tertiary referral center from January 2008 till December 2018 and analyzed it with descriptive statistics. Only patients with a complete data set were included in the further analysis. Odds ratio’s for moderate-to-severe and sight-threatening GO in relation to age, sex and smoking were calculated by means of multivariate logistic regression models.ResultsWe evaluated the data of 4260 patient with GO and complete data sets. Most of these were women (83%). There were no significant differences between male and female patients regarding smoking habits and thyroid treatment. Men were significantly older at initial manifestation of TED (51.8 vs. 49.9y, p<0.01) and showed significant more often severe stages (61% vs. 53%, p<0.0001). Therefore, they needed significantly more intense treatment with steroids, irradiation, orbital decompression and muscle surgery. In multivariate logistic regression analyses age (OR 0.97, 95% CI:0.97-0.98, p<0.0001), male sex (OR 1.64, 95% CI:1.38-1.9, p<0.0001), smoking (OR 1.19, 95% CI:1.04-1.36, p=0.01), Grave’s disease (OR 1.55, 95% CI:1.26-1.90, p<0.0001) and history of radioiodine treatment (RAI) (OR 2.44, 95% CI:2.10-2.86, p<0.0001) showed an significant association with severe stages of GO.DiscussionOur retrospective analysis showed once more that women are more often afflicted by GO. In contrast, men seem to be more severely afflicted and in need of anti-inflammatory and surgical treatments. This might be due to a different approach to the health system and resilience to GO specific symptoms, as well as previously described worse thyroid control. Estrogen mediated effects might also play a role as in other autoimmune diseases and should be subject of further trials. Besides the biological sex, smoking could again be confirmed as serious risk factor for severe GO. Of note, RAI was associated with more severe stages of GO, which should be subject to further investigation.

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Section: Discussionsupporting

confidence: 91%

Influence of biological sex, age and smoking on Graves’ orbitopathy – a ten-year tertiary referral center analysis

et al. 2023

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“… 26–29 Besides, macrophage infiltration also play a significant role in the pathogenesis, which prompted the production of hypoxia marker HIF-1α and inflammatory cytokines. 30 , 31 In consequence, T lymphocytes/Macrophage/OF interaction results in constant inflammation and tissue remodeling. Indeed, in our plasmid-immunized mice model, the orbital tissue and thyroid gland showed different degrees of T lymphocyte and macrophage infiltration, although only 4/6 mice developed ocular symptoms, all of them had varying degrees of elevated thyroid hormone and antibody levels.…”

Section: Discussionmentioning

confidence: 99%

TSG6 Plays a Role in Improving Orbital Inflammatory Infiltration and Extracellular Matrix Accumulation in TAO Model Mice

He¹,

Chen²,

Wang³

et al. 2023

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Introduction TSG-6 plays a wide anti-inflammatory and therapeutic role in a variety of autoimmune diseases as the key mediator of mesenchymal stem cells (MSCs). Purpose We aimed to test whether TSG-6 could exert similar effects as MSCS in TAO via establishing TAO animal model immunized by hTSHR-A subunit plasmid. Material and Methods We tested the expression level of TSG-6 on intraconal orbital fat from controls and patients with TAO. We established a stable thyroid-associated ophthalmopathy animal model by immunizing 6-week-old female Balb/c mice with recombination hTSHR-A subunit plasmid. After four immunizations, TSG-6 or dexamethasone was injected through the tail vein. The effects of the drugs on body weight, thyroid function, orbital inflammation, fibrosis and lipogenesis were observed. Results The expression of TSG-6 in the orbital tissues of TAO patient is lower than that of normal people. In our animal model, mice showed weight loss, higher TT4 and TSHR antibody levels, and ocular symptoms such as inflammation and proptosis. TSG-6 can reduce ocular fibrosis and lipogenesis by inhibiting the infiltration of CD3+ T lymphocytes and macrophages in the mouse model of thyroid associated ophthalmopathy. Compared with dexamethasone, TSG-6 showed comparable anti-inflammatory effect, moreover, it has given a better performance in inhibiting adipogenesis. Conclusion It was demonstrated that TSG-6 has a considerable positive impact on improving eye symptoms of TAO mice, which could be a novel candidate for the early treatment of TAO.

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“…These two pathomechanisms lead clinically to swollen extraocular muscles and exophthalmos. Since the volume increases occur in a bony-limited orbit, it can lead to more or less compression of the orbit depending on the strength of the orbital ligaments, impairment of orbital venous and lymphatic outflow and tissue hypoxia ( 61 , 62 ).…”

Section: Thyroid Eye Diseasementioning

confidence: 99%

Sphingolipids in thyroid eye disease

et al. 2023

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Graves’ disease (GD) is caused by an autoimmune formation of autoantibodies and autoreactive T-cells against the thyroid stimulating hormone receptor (TSHR). The autoimmune reaction does not only lead to overstimulation of the thyroid gland, but very often also to an immune reaction against antigens within the orbital tissue leading to thyroid eye disease, which is characterized by activation of orbital fibroblasts, orbital generation of adipocytes and myofibroblasts and increased hyaluronan production in the orbit. Thyroid eye disease is the most common extra-thyroidal manifestation of the autoimmune Graves’ disease. Several studies indicate an important role of sphingolipids, in particular the acid sphingomyelinase/ceramide system and sphingosine 1-phosphate in thyroid eye disease. Here, we discuss how the biophysical properties of sphingolipids contribute to cell signaling, in particular in the context of thyroid eye disease. We further review the role of the acid sphingomyelinase/ceramide system in autoimmune diseases and its function in T lymphocytes to provide some novel hypotheses for the pathogenesis of thyroid eye disease and potentially allowing the development of novel treatments.

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Macrophage-Orbital Fibroblast Interaction and Hypoxia Promote Inflammation and Adipogenesis in Graves’ Orbitopathy

Cited by 10 publications

References 57 publications

Influence of biological sex, age and smoking on Graves’ orbitopathy – a ten-year tertiary referral center analysis

Influence of biological sex, age and smoking on Graves’ orbitopathy – a ten-year tertiary referral center analysis

TSG6 Plays a Role in Improving Orbital Inflammatory Infiltration and Extracellular Matrix Accumulation in TAO Model Mice

Sphingolipids in thyroid eye disease

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