Perilipin 2–positive mononuclear phagocytes accumulate in the diabetic retina and promote PPARγ-dependent vasodegeneration
Guillaume Blot, … , Florian Sennlaub, Xavier Guillonneau
Guillaume Blot, … , Florian Sennlaub, Xavier Guillonneau
Published October 2, 2023
Citation Information: J Clin Invest. 2023;133(19):e161348. https://doi.org/10.1172/JCI161348.
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Research Article Inflammation Ophthalmology

Perilipin 2–positive mononuclear phagocytes accumulate in the diabetic retina and promote PPARγ-dependent vasodegeneration

Abstract

Type 2 diabetes mellitus (T2DM), characterized by hyperglycemia and dyslipidemia, leads to nonproliferative diabetic retinopathy (NPDR). NPDR is associated with blood-retina barrier disruption, plasma exudates, microvascular degeneration, elevated inflammatory cytokine levels, and monocyte (Mo) infiltration. Whether and how the diabetes-associated changes in plasma lipid and carbohydrate levels modify Mo differentiation remains unknown. Here, we show that mononuclear phagocytes (MPs) in areas of vascular leakage in DR donor retinas expressed perilipin 2 (PLIN2), a marker of intracellular lipid load. Strong upregulation of PLIN2 was also observed when healthy donor Mos were treated with plasma from patients with T2DM or with palmitate concentrations typical of those found in T2DM plasma, but not under high-glucose conditions. PLIN2 expression correlated with the expression of other key genes involved in lipid metabolism (ACADVL, PDK4) and the DR biomarkers ANGPTL4 and CXCL8. Mechanistically, we show that lipid-exposed MPs induced capillary degeneration in ex vivo explants that was inhibited by pharmaceutical inhibition of PPARγ signaling. Our study reveals a mechanism linking dyslipidemia-induced MP polarization to the increased inflammatory cytokine levels and microvascular degeneration that characterize NPDR. This study provides comprehensive insights into the glycemia-independent activation of Mos in T2DM and identifies MP PPARγ as a target for inhibition of lipid-activated MPs in DR.

Authors

Guillaume Blot, Rémi Karadayi, Lauriane Przegralek, Thérèse-Marie Sartoris, Hugo Charles-Messance, Sébastien Augustin, Pierre Negrier, Frédéric Blond, Frida Paulina Muñiz-Ruvalcaba, David Rivera-de la Parra, Lucile Vignaud, Aude Couturier, José-Alain Sahel, Niyazi Acar, Aida Jimenez-Corona, Cécile Delarasse, Yonathan Garfias, Florian Sennlaub, Xavier Guillonneau

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Figure 1

PLIN2+ MPs are found in regions with retinal plasma leakage in a patient with DR.

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PLIN2+ MPs are found in regions with retinal plasma leakage in a patient...
(A–G) Representative immunofluorescence (IF) images of human flat-mounted retinas from 4 postmortem DM donors. (A) IF staining of ALB (plasma protein) and COL4 (vessels) within a healthy vasculature area of human retina. Scale bar: 200 μm. (B) IF staining for ALB and COL4 within an area showing vascular leakage. Scale bar: 200 μm. (C) IF staining for ALB, IBA1, and PLIN2 within an area with a leaking microaneurysm. Scale bar: 40 μm. (D) IF staining for COL4, IBA1 (MPs), and PLIN2 (neutral lipid droplets) within an area with a microaneurysm. Scale bar: 30 μm. (E and F) IF staining for IBA1 and PLIN2 and labeling with UEA1 (vessels). (E) IF staining for IBA1 and PLIN2. The arrows show a PLIN2– (blue) and a PLIN2+ (red) MP within the same region. Scale bar: 10 μm. (F) Representative image outside the area with the microaneurysms. Scale bar: 200 μm. (G) Representative image within the area of the microaneurysms. (H) Total MP count and PLIN2+ MP count around microaneurysms in 4 different DM donors (each color represents a different donor). (I) Percentage of PLIN2+ MPs within microaneurysms containing at least 1 PLIN2+ MP. (J) Schematic depiction of a ruptured retinal microaneurysm leading to plasma leakage in a DR retina.