Intersection of Chemokine and TSH Receptor Pathways in Human Fibrocytes: Emergence of CXCL-12/CXCR4 Cross Talk Potentially Relevant to Thyroid-Associated Ophthalmopathy

• Published in: Endocrinology (Philadelphia) Vol. 157; no. 10; pp. 3779 - 3787
• Main Authors: Fernando, Roshini, Atkins, Stephen J, Smith, Terry J
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01-10-2016; Oxford University Press
• Subjects: CD34 antigen; Cells (biology); Cells, Cultured; Chemokine CXCL12 - metabolism; Chemokine receptors; Chemokines; CXCR4 protein; Eye diseases; Fibrosis; Graves disease; Graves Ophthalmopathy - metabolism; Humans; Interleukin-6 - metabolism; Ligands; Monocyte-Macrophage Precursor Cells - metabolism; Monocytes; Original Research; Pathogenesis; Progenitor cells; Receptor Cross-Talk; Receptors, CXCR4 - metabolism; Receptors, Thyrotropin - metabolism; Thyroid; Thyroid gland; Thyroid-stimulating hormone; Thyroid-stimulating hormone receptors
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2016-1382

Fibrocytes are monocyte progenitor cells that have been implicated in normal and pathological tissue remodeling. Among the prominent chemokine receptors expressed by these cells is CXC motif receptor 4 (CXCR4), which, with its cognate ligand CXCL motif ligand 12 (CXCL-12), directs fibrocytes to sites of fibrosis. Fibrocytes have been implicated in the pathogenesis of thyroid-associated ophthalmopathy, the ocular manifestation of Graves' disease (GD), by virtue of their unique accumulation as CD34+ orbital fibroblasts (OFs). Fibrocytes also express high levels of functional TSH receptor (TSHR). Here, we determined CXCL-12 and CXCR4 expression in fibrocytes and GD-OF and whether that pathway interacts with TSHR. CXCL-12 is highly expressed in GD-OF, whereas CXCR4 levels are dramatically higher in fibrocytes. Levels of these proteins are differentially regulated by TSH in a cell type-specific manner. Further, CXCL-12 enhances the induction by TSH of IL-6 in fibrocytes but attenuates this induction in GD-OF. In contrast, in pure CD34+ OF, the interplay between TSH and CXCL-12 reverts to that observed in fibrocytes. Our results indicate that CXCL-12 enhances TSH actions in fibrocytes but inhibits them in GD-OF, a dichotomy imposed by factors emanating from CD34− OF. They also suggest a potentially important modulatory role for CD34− OF in determining the factors that influence pathological TSHR signaling in the TAO orbit.