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ResearchIn-Press PreviewOphthalmology Open Access | 10.1172/JCI180904

Retinal perivascular macrophages regulate immune cell infiltration during neuroinflammation in mouse models of ocular disease

Jacob K. Sterling,1 Amrita Rajesh,2 Steven Droho,2 Joyce Gong,2 Andrew L. Wang,2 Andrew P. Voigt,2 C. Elysse Brookins,2 and Jeremy A. Lavine2

1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Ophthalmology, Northwestern University, Chicago, United States of America

Find articles by Sterling, J. in: JCI | PubMed | Google Scholar

1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Ophthalmology, Northwestern University, Chicago, United States of America

Find articles by Rajesh, A. in: JCI | PubMed | Google Scholar

1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Ophthalmology, Northwestern University, Chicago, United States of America

Find articles by Droho, S. in: JCI | PubMed | Google Scholar

1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Ophthalmology, Northwestern University, Chicago, United States of America

Find articles by Gong, J. in: JCI | PubMed | Google Scholar

1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Ophthalmology, Northwestern University, Chicago, United States of America

Find articles by Wang, A. in: JCI | PubMed | Google Scholar

1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Ophthalmology, Northwestern University, Chicago, United States of America

Find articles by Voigt, A. in: JCI | PubMed | Google Scholar |

1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Ophthalmology, Northwestern University, Chicago, United States of America

Find articles by Brookins, C. in: JCI | PubMed | Google Scholar

1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Ophthalmology, Northwestern University, Chicago, United States of America

Find articles by Lavine, J. in: JCI | PubMed | Google Scholar

Published August 29, 2024 - More info

J Clin Invest. https://doi.org/10.1172/JCI180904.
Copyright © 2024, Sterling et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 29, 2024 - Version history
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Abstract

The blood-retina barrier (BRB), which is disrupted in diabetic retinopathy (DR) and uveitis, is an important anatomical characteristic of the retina, regulating nutrient, waste, water, protein, and immune cell flux. The BRB is composed of endothelial cell tight junctions, pericytes, astrocyte end feet, a collagen basement membrane, and perivascular macrophages. Despite the importance of the BRB, retinal perivascular macrophage function remains unknown. We found that retinal perivascular macrophages reside on post-capillary venules in the superficial vascular plexus and express MHCII. Using single-cell RNA-sequencing, we found that perivascular macrophages express a pro-chemotactic transcriptome and identified Pf4/CXCL4 as a perivascular macrophage marker. We used Pf4Cre mice to specifically deplete perivascular macrophages. To model retinal inflammation, we performed intraocular CCL2 injections. Ly6C+ monocytes crossed the BRB proximal to perivascular macrophages. Depletion of perivascular macrophages severely hampered Ly6C+ monocyte infiltration. These data suggest that retinal perivascular macrophages orchestrate immune cell migration across the BRB, with implications for inflammatory ocular diseases including DR and uveitis.

Graphical Abstract
graphical abstract
Supplemental material

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View Supplemental Table 2. Differential expression analysis between each macrophage cluster and all other cells. Each tab denotes a cluster of cells including gene names, cluster number, adjusted p-value (p_val_adj), percent of cells expressing gene (pct.1 = current cluster, pct.2 = all other clusters), fold change (avg_logFC = natural log fold change), and raw p-value (p_val).

View Supplemental Table 3. Gene ontology (GO) outputs for up-regulated genes from each macrophage subtype. Each tab is from a cluster, includig description of GO term, p-value, FDR q-value, fold enrichment, number of genes expressed in macrophages (N), number of genes in GO term (B), number of differentially expressed genes (n), number of differentially expressed genes in the GO term (b), and the specific genes that were differentially expressed in the GO term. Any cluster not included had no significant GO enrichment.

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