{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T14:38:11Z","timestamp":1788964691141,"version":"build-2803163510"},"reference-count":61,"publisher":"The Endocrine Society","issue":"2","license":[{"start":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T00:00:00Z","timestamp":1670371200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The inflammatory eye disease Graves\u2019 orbitopathy (GO) is the main complication of autoimmune Graves\u2019 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-1\u03b1, the MQ marker CD68, and inflammatory cytokines TNF\u03b1, CCL2, CCL5, and CCL20 in GO biopsies. Hypoxia stimulated GO tissues to release TNF\u03b1, CCL2, and CCL20 as measured by multiplex enzyme-linked immunosorbent assay (ELISA). Further, TNF\u03b1 and hypoxia stimulated the expression of HIF-1\u03b1, CCL2, CCL5, and CCL20 in OF derived from GO tissues. Immunofluorescence confirmed that TNF\u03b1-positive MQ were present in the GO tissues. Thus, interaction of M1-MQ with OF under hypoxia also induced HIF-1\u03b1, CCL2, and CCL20 in OF. Inflammatory inhibitors etanercept or dexamethasone prevented the induction of HIF-1\u03b1 and release of CCL2 and CCL20. Moreover, co-culture of M1-MQ\/OF under hypoxia enhanced adipogenic differentiation and adiponectin secretion. Dexamethasone and HIF-1\u03b1 inhibitor PX-478 reduced this effect. Our findings indicate that GO fat tissues are characterized by an inflammatory and hypoxic milieu where TNF\u03b1-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-1\u03b1 reduction could be an effective treatment option.<\/jats:p>","DOI":"10.1210\/endocr\/bqac203","type":"journal-article","created":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T12:47:01Z","timestamp":1670417221000},"source":"Crossref","is-referenced-by-count":26,"title":["Macrophage-Orbital Fibroblast Interaction and Hypoxia Promote Inflammation and Adipogenesis in Graves\u2019 Orbitopathy"],"prefix":"10.1210","volume":"164","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3380-2635","authenticated-orcid":false,"given":"Gina-Eva","family":"G\u00f6rtz","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Molecular Ophthalmology Group, University Hospital Essen , 45147 Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8077-3227","authenticated-orcid":false,"given":"Svenja","family":"Philipp","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Molecular Ophthalmology Group, University Hospital Essen , 45147 Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Bruderek","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, University Hospital Essen , 45147 Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Jesenek","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen , 45147 Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mareike","family":"Horstmann","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Molecular Ophthalmology Group, University Hospital Essen , 45147 Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0166-2204","authenticated-orcid":false,"given":"Yoshiyuki","family":"Henning","sequence":"additional","affiliation":[{"name":"Institute of Physiology, University Hospital Essen , 45147 Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0807-7689","authenticated-orcid":false,"given":"Michael","family":"Oeverhaus","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Molecular Ophthalmology Group, University Hospital Essen , 45147 Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"Daser","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, University Hospital Essen , 45147 Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0180-1112","authenticated-orcid":false,"given":"Nikolaos E","family":"Bechrakis","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Molecular Ophthalmology Group, University Hospital Essen , 45147 Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8971-1444","authenticated-orcid":false,"given":"Anja","family":"Eckstein","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Molecular Ophthalmology Group, University Hospital Essen , 45147 Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2702-4163","authenticated-orcid":false,"given":"Sven","family":"Brandau","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, University Hospital Essen , 45147 Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Utta","family":"Berchner-Pfannschmidt","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Molecular Ophthalmology Group, University Hospital Essen , 45147 Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2022,12,7]]},"reference":[{"issue":"2","key":"2022122308510468700_bqac203-B1","first-page":"185","article-title":"Graves\u2019 disease","volume":"376","author":"Smith","year":"2017","journal-title":"N Engl J Med"},{"issue":"4S Suppl 1","key":"2022122308510468700_bqac203-B2","doi-asserted-by":"crossref","first-page":"S75","DOI":"10.1097\/IOP.0000000000001148","article-title":"Surgical treatment of diplopia in graves orbitopathy patients","volume":"34","author":"Eckstein","year":"2018","journal-title":"Ophthalmic Plast Reconstr 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