Retinal perivascular macrophages regulate immune cell infiltration during neuroinflammation in mouse models of ocular disease
Jacob K. Sterling, Amrita Rajesh, Steven Droho, Joyce Gong, Andrew L. Wang, Andrew P. Voigt, C. Elysse Brookins, Jeremy A. Lavine
Jacob K. Sterling, Amrita Rajesh, Steven Droho, Joyce Gong, Andrew L. Wang, Andrew P. Voigt, C. Elysse Brookins, Jeremy A. Lavine
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Research Article Ophthalmology

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

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 resided on postcapillary venules in the superficial vascular plexus and expressed MHC class II. Using single-cell RNA-Seq, we found that perivascular macrophages expressed a prochemotactic transcriptome and identified platelet factor 4 (Pf4, also known as 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.

Authors

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

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Figure 6

Perivascular macrophages correlate with Ly6C+ inflammatory cell infiltration.

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Perivascular macrophages correlate with Ly6C+ inflammatory cell infiltra...
(A) Schematic showing approximate location for intravitreal injections of CCL2. (B) Frequency histogram of each cell type and their distance from the optic nerve. Significant overlap was found between the distribution of perivascular macrophages and Ly6C+ cells using a transformation of the Kolmogorov-Smirnov test. n = 2,998 cells. (C) Overview representative image of Ly6C+ cell infiltration at the superficial vascular plexus. Scale bar: 50 μm. (D–F) Zoomed-in representative images identifying Ly6C+ cells close to the optic nerve head where most perivascular macrophages (white arrowheads) resided in Tmem119GFP mice. Scale bar: 200 μm. (G and H) Zoomed-in representative images of cells from Pf4-zsGreen mice showing close association between Ly6C+ monocytes (red cell, white arrowhead) and Pf4+ perivascular macrophages. Scale bar: 50 μm.