1. Academic Validation
  2. Macrophage-orbital fibroblast interaction and hypoxia promote inflammation and adipogenesis in Graves´ orbitopathy

Macrophage-orbital fibroblast interaction and hypoxia promote inflammation and adipogenesis in Graves´ orbitopathy

  • Endocrinology. 2022 Dec 7;bqac203. doi: 10.1210/endocr/bqac203.
Gina-Eva Görtz 1 Svenja Philipp 1 Kirsten Bruderek 2 Christoph Jesenek 3 Mareike Horstmann 1 Yoshiyuki Henning 4 Michael Oeverhaus 1 Anke Daser 2 Nikolaos E Bechrakis 1 Anja Eckstein 1 Sven Brandau 2 Utta Berchner-Pfannschmidt 1
Affiliations

Affiliations

  • 1 Department of Ophthalmology, Molecular Ophthalmology Group, University Hospital Essen, Essen, Germany.
  • 2 Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany.
  • 3 Department of Cardiology and vascular medicine, West German Heart and Vascular center, University Hospital Essen, Essen, Germany.
  • 4 Institute of Physiology, University Hospital Essen, Essen, Germany.
Abstract

The inflammatory eye disease Graves' orbitopathy (GO) is the main complication of autoimmune Graves' disease. In previous studies we have shown that hypoxia plays an important role for progression of GO. Hypoxia can maintain inflammation by attracting inflammatory cells such as macrophages (MQ). Herein, we investigated the interaction of MQ and orbital fibroblasts (OF) in context of inflammation and hypoxia. We detected elevated levels of the hypoxia marker HIF-1α, the MQ marker CD68, and inflammatory cytokines TNFα, CCL2, CCL5 and CCL20 in GO biopsies. Hypoxia stimulated GO tissues to release of TNFα, CCL2, and CCL20 as measured by multiplex ELISA. Further, TNFα and hypoxia stimulated the expression of HIF-1α, CCL2, CCL5 and CCL20 in OF derived from GO tissues. Immunofluorescence confirmed that TNFα positive MQ were present in the GO tissues. Thus, interaction of M1-MQ with OF under hypoxia also induced HIF-1α, CCL2 and CCL20 in OF. Inflammatory inhibitors etanercept or dexamethasone prevented the induction of HIF-1α and release of CCL2 and CCL20. Moreover, co-culture of M1-MQ/OF under hypoxia enhanced adipogenic differentiation and Adiponectin secretion. Dexamethasone and HIF-1α Inhibitor PX-478 reduced this effect. Our findings indicate that GO fat tissues are characterized by an inflammatory and hypoxic milieu where TNFα positive MQ are present. Hypoxia and interaction of M1-MQ with OF led to enhanced secretion of chemokines, elevated hypoxic signaling and adipogenesis. In consequence, M1-MQ/OF interaction results in constant inflammation and tissue remodeling. A combination of anti-inflammatory treatment and HIF-1α reduction could be an effective treatment option.

Keywords

Adipogenesis; Graves’ orbitopathy; Hypoxia; Macrophages; Orbital fibroblasts; TNFα.

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