Immunomodulatory stromal cell interactions in the eye

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Science Translational Medicine  08 Apr 2020:
Vol. 12, Issue 538, eabb5668
DOI: 10.1126/scitranslmed.abb5668


Single-cell sequencing of eye stroma reveals cell-cell interactions essential for suppressing ocular inflammation.

The complex cellular composition and highly ordered structure of the eye enables sensing of incoming light and transformation of the stimuli to electrochemical signals understandable by the nervous system. Inflammation can damage this arrangement, resulting in loss of vision. Ocular immune privilege prevents potentially pathologic inflammatory responses in the eye and promotes immunologic tolerance. Although this immune privilege property is well recognized, the underlying mechanisms are incompletely understood.

Lehmann et al. performed single-cell RNA sequencing of choroid-associated cells from the eyes of adult mice to characterize cell types comprising the associated stroma. They identified multiple previously unrecognized subtypes of choroid endothelial cells (ECs), as well as an uncharacterized population of mesenchymal stem cell (MSC)–like cells. The precise single-cell examination of choroidal ECs identified Indian Hedgehog (Ihh), a secreted Hedgehog family protein, as specifically highly expressed by choriocapillaris-associated ECs expressing high levels of Kdr (vascular endothelial growth factor receptor 2). Analysis of single-cell transcriptome data for Hedgehog-dependent gene expression identified a GLI family zinc finger 1 (GLI1)–expressing MSC-like cell as the target for Indian Hedgehog. To test the potential effect of the putative KdrhighEC–Indian Hedgehog–GLI1+MSC circuit, the authors generated an EC-specific inducible Ihh deletion. Specific deletion of Ihh expression in ECs resulted in down-regulation of Hedgehog-dependent gene expression in the GLI1+MSCs and downstream Hedgehog-independent effects. Hedgehog-dependent signaling in MSCs inhibited the expression of pro-inflammatory factors, including interferon (IFN)–β, IFN-γ, interleukin (IL)–6R, IL-1R1, STAT1, and nuclear factor κB. Deletion of this response in vivo reduced recruitment of mast cells and anti-inflammatory M2 macrophages to the eye and exaggerated pathologic inflammatory response to NaIO3-induced retinal injury in mice, demonstrating the physiological importance of this regulatory circuit.

These findings identify a multicell regulatory circuit as a mechanism underlying ocular immune privilege. Discovery of this pathway reveals potential targets for immunomodulation in the eye, as well as Ihh-dependent and MSC-mediated mechanisms in other inflammatory diseases. These findings are limited by a need for confirmation in human tissue and investigation of this regulatory mechanism in inflammatory eye diseases. However, these targets for immunomodulation in the eye may lead to improved approaches for treatment of inflammation-associated blinding diseases, such as uveitis, diabetic retinopathy, and age-related macular degeneration.

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