The Role of Adipsin, Complement Factor D, in the Pathogenesis of Graves’ Orbitopathy

Byeon, Hyeong Ju; Chae, Min Kyung; Ko, Jeong-Sik; Lee, Mi Kyung; Kikkawa, Don O.; Jang, Sun Young; Yoon, Jin Sook

doi:10.1167/iovs.64.11.13

Cited by 3 publications

(1 citation statement)

References 56 publications

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“…Activation of TED-OFs by CD40L or IGF-1 causes fibroblasts to differentiate into adipocytes, leading to increased synthesis and secretion of Adipsin. This further increases the expression of downstream cytokines, including IL-6, IL-8, PGE2, ICAM-1, and CCL2 ( 73 ). In addition, there is a notable elevation in the expression of sphingosine-1-phosphate (S1P) in the orbital tissues of patients with TED.…”

Section: Specific Role Of Immune Checkpoints In the Pathogenesis Of Tedmentioning

confidence: 99%

Immune checkpoints: new insights into the pathogenesis of thyroid eye disease

Shu,

Shao,

Chen

et al. 2024

Front. Immunol.

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Thyroid eye disease (TED) is a disfiguring autoimmune disease characterized by changes in the orbital tissues and is caused by abnormal thyroid function or thyroid-related antibodies. It is the ocular manifestation of Graves’ disease. The expression of thyroid-stimulating hormone receptor (TSHR) and the insulin-like growth factor-1 receptor (IGF-1 R) on the cell membrane of orbital fibroblasts (OFs) is responsible for TED pathology. Excessive inflammation is caused when these receptors in the orbit are stimulated by autoantibodies. CD34+ fibrocytes, found in the peripheral blood and orbital tissues of patients with TED, express immune checkpoints (ICs) like MHC II, B7, and PD-L1, indicating their potential role in presenting antigens and regulating the immune response in TED pathogenesis. Immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment. However, it can also lead to the occurrence of TED in some instances, suggesting the abnormality of ICs in TED. This review will examine the overall pathogenic mechanism linked to the immune cells of TED and then discuss the latest research findings on the immunomodulatory role of ICs in the development and pathogenesis of TED. This will offer fresh perspectives on the study of pathogenesis and the identification of potential therapeutic targets.

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Section: Specific Role Of Immune Checkpoints In the Pathogenesis Of Tedmentioning

confidence: 99%

Immune checkpoints: new insights into the pathogenesis of thyroid eye disease

Shu,

Shao,

Chen

et al. 2024

Front. Immunol.

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Role of Lysyl Oxidase-Like Protein 3 in the Pathogenesis of Graves’ Orbitopathy in Orbital Fibroblasts

Park,

Choi,

Park

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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Purpose The lysyl oxidase (LOX) family has been implicated in the pathogenesis of diseases caused by inflammation and fibrosis. Therefore, we aimed to examine the role of lysyl oxidase-like protein 3 (LOXL3) in Graves’ orbitopathy (GO) pathogenesis and its potential as a treatment target. Methods Quantitative real-time polymerase chain reaction compared the transcript levels of the five LOX family subtypes in orbital tissue explants obtained from patients with GO ( n = 18) and healthy controls ( n = 15). The effects of LOXL3 inhibition on interleukin (IL)-1β-induced proinflammatory cytokines, transforming growth factor (TGF)-β-induced profibrotic proteins, intracellular signaling molecules, and adipogenic markers were evaluated using Western blotting. Adipogenic differentiation was identified using Oil Red O staining. Results LOX and LOXL3 transcript levels were high in GO tissues. Stimulation with IL-1β, TGF-β, and insulin-like growth factor-1 significantly increased LOXL3 messenger RNA expression in GO fibroblasts. Furthermore, silencing LOXL3 attenuated the IL-1β-induced production of proinflammatory cytokines (IL-6, IL-8, and intercellular adhesion molecule-1) and TGF-β-induced production of profibrotic proteins (fibronectin, collagen 1α, and alpha-smooth muscle actin). It also reduced the IL-1β or TGF-β-induced expression of phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells, protein kinase B, extracellular signal-regulated kinase, and c-Jun N-terminal kinase. Additionally, LOXL3 silencing suppressed adipocyte differentiation and the expression of adipogenic transcription factors (leptin, AP-2, peroxisome proliferator-activated receptor gamma, and CCAAT/enhancer-binding protein). Conclusions LOXL3 is crucial in GO pathogenesis. LOXL3 inhibition reduced inflammatory cytokine production, fibrotic protein expression, and fibroblast differentiation into adipocytes. This study highlights LOXL3 as a potential therapeutic target for GO.

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Therapeutic role of histone deacetylase inhibition in an in vitro model of Graves' orbitopathy

Byeon,

Choi,

Kikkawa

et al. 2024

Mol Med Rep

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Graves' orbitopathy (GO), a manifestation of Graves' disease, is characterized by orbital fibroblast-induced inflammation, leading to fibrosis or adipogenesis. Histone deacetylase (HDAC) serves a central role in autoimmune diseases and fibrosis. The present study investigated HDAC inhibition in orbital fibroblasts from patients with GO to evaluate its potential as a therapeutic agent. Primary cultured orbital fibroblasts were treated with an HDAC inhibitor, panobinostat, under the stimulation of IL-1β, TGF-β or adipogenic medium. Inflammatory cytokines, and fibrosis- and adipogenesis-related proteins were analyzed using western blotting. The effects of panobinostat on HDAC mRNA expression were measured in GO orbital fibroblasts, and specific HDACs were inhibited using small interfering RNA transfection. Panobinostat significantly reduced the IL-1β-induced production of inflammatory cytokines and TGF-β-induced production of fibrosis-related proteins. It also suppressed adipocyte differentiation and adipogenic transcription factor production. Furthermore, it significantly attenuated HDAC7 mRNA expression in GO orbital fibroblasts. In addition, the silencing of HDAC7 led to anti-inflammatory and anti-fibrotic effects. In conclusion, by inhibiting HDAC7 gene expression, panobinostat may suppress the production of inflammatory cytokines, profibrotic proteins and adipogenesis in GO orbital fibroblasts. The present in vitro study suggested that HDAC7 could be a potential therapeutic target for inhibiting the inflammatory, adipogenic and fibrotic mechanisms of GO.

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The Role of Adipsin, Complement Factor D, in the Pathogenesis of Graves’ Orbitopathy

Cited by 3 publications

References 56 publications

Immune checkpoints: new insights into the pathogenesis of thyroid eye disease

Immune checkpoints: new insights into the pathogenesis of thyroid eye disease

Role of Lysyl Oxidase-Like Protein 3 in the Pathogenesis of Graves’ Orbitopathy in Orbital Fibroblasts

Therapeutic role of histone deacetylase inhibition in an in vitro model of Graves' orbitopathy

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