title: Intersection of Chemokine and TSH Receptor Pathways in Human Fibrocytes: Emergence of CXCL-12/CXCR4 Cross Talk Potentially Relevant to Thyroid-Associated Ophthalmopathy.
abstract: 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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kellogg Eye Center and Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48105.
authors.forename: Roshini
authors.initials: R
authors.lastname: Fernando
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kellogg Eye Center and Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48105.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Atkins
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kellogg Eye Center and Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48105.
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Smith
mesh_terms: D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism*; D049970:Graves Ophthalmopathy / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D055017:Monocyte-Macrophage Precursor Cells / Q000378:metabolism*; D020239:Receptor Cross-Talk; D019718:Receptors, CXCR4 / Q000378:metabolism*; D011989:Receptors, Thyrotropin / Q000378:metabolism*
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D015850:Interleukin-6; D019718:Receptors, CXCR4; D011989:Receptors, Thyrotropin