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TSH-receptor-expressing fibrocytes and thyroid-associated ophthalmopathy

Nature Reviews Endocrinology volume 11, pages 171–181 (2015)Cite this article

Subjects

Key Points

  • Thyroid-associated ophthalmopathy (TAO) is a manifestation of the systemic malady Graves disease

  • Fibrocytes derived from monocyte progenitor cells apparently infiltrate the orbit in patients with TAO

  • By virtue of their diverse repertoire of molecule expression and responses to microenvironmental cues, fibrocytes could help orchestrate orbital tissue activation and remodelling

  • The signalling complex comprising TSHR and IGF-1R seems to contribute to activation of fibrocytes and orbital fibroblasts, and might be a target for novel therapeutic strategies for TAO

  • The involvement of fibrocytes in orbital Graves disease might offer clues to clarify the participation of these cells in other autoimmune inflammatory diseases

Abstract

Thyroid-associated ophthalmopathy (TAO) is a vexing and undertreated ocular component of Graves disease in which orbital tissues undergo extensive remodelling. My colleagues and I have introduced the concept that fibrocytes expressing the haematopoietic cell antigen CD34 (CD34+ fibrocytes), which are precursor cells of bone-marrow-derived monocyte lineage, express the TSH receptor (TSHR). These cells also produce several other proteins whose expression was traditionally thought to be restricted to the thyroid gland. TSHR-expressing fibrocytes in which the receptor is activated by its ligand generate extremely high levels of several inflammatory cytokines. Acting in concert with TSHR, the insulin-like growth factor 1 receptor (IGF-1R) expressed by orbital fibroblasts and fibrocytes seems to be necessary for TSHR-dependent cytokine production, as anti-IGF-1R blocking antibodies attenuate these proinflammatory actions of TSH. Furthermore, circulating fibrocytes are highly abundant in patients with TAO and seem to infiltrate orbital connective tissues, where they might transition to CD34+ fibroblasts. My research group has postulated that the infiltration of fibrocytes into the orbit, their unique biosynthetic repertoire and their proinflammatory and profibrotic phenotype account for the characteristic properties exhibited by orbital connective tissues that underlie susceptibility to TAO. These insights, which have emerged in the past few years, might be of use in therapeutically targeting pathogenic orbit-infiltrating fibrocytes selectively by utilizing novel biologic agents that interfere with TSHR and IGF-1R signalling.

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Figure 1: Identification of CD34+ fibrocytes in patients with Graves disease and TAO.
Figure 2: Analysis of TSHR and thyroglobulin expression by human fibrocytes and fibroblasts.
Figure 3: TSHR expression on fibrocytes generated from peripheral blood mononuclear cells can initiate cytokine production.
Figure 4: mRNAs encoding proteins previously thought to be thyroid-specific are detectable in fibrocytes and CD34+ orbital fibroblasts.
Figure 5: Schematic representation of a theoretical model for TAO in which CD34+ fibrocytes are released from the bone marrow and infiltrate orbital connective tissues.

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Acknowledgements

The author gratefully acknowledges the assistance of L. Polonsky and J. Piernicka in the preparation of this manuscript before submission. This work was supported in part by NIH grant EY08976, Center for Vision grant EY007003 from the National Eye Institute, NIH, USA, and unrestricted grants from Research to Prevent Blindness and the Bell Charitable Foundation.

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  1. Department of Ophthalmology and Visual Sciences, Room 7112, Brehm Tower, Kellogg Eye Center, University of Michigan Medical School, 1000 Wall Street, Ann Arbor, 48105, MI, USA

    Terry J. Smith

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Smith, T. TSH-receptor-expressing fibrocytes and thyroid-associated ophthalmopathy. Nat Rev Endocrinol 11, 171–181 (2015). https://doi.org/10.1038/nrendo.2014.226

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