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 3

T2DM plasma, but not glucose, induces a lipid-associated phenotype in MPs.

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T2DM plasma, but not glucose, induces a lipid-associated phenotype in MP...
(A) Schematic representation of donor phenotyping and group attribution, plasma preparation, and naive Mo treatment. (B and C) RT-qPCR quantification of healthy donor naive Mos treated for 18 hours with donor plasma from ND individuals (n = 10 [blue dots]) or patients with T2DM (n = 27, no DR [light pink dots], NPDR [pink dots], PDR [dark red dots]). (B) Violin plot representation of the relative expression of the indicated genes in response to individual donor plasma exposure. Dashed lines represent the median and quartiles. P values were determined using a 2-tailed Mann-Whitney U test. (C) Simple linear regression representation of PDK4, ACADVL, ANGPTL4, and CXCL8 (y axis) and PLIN2 expression (x axis). Correlations between expression levels were analyzed using Spearman’s correlation; the linear regression equation, Spearman’s r [95% CI], and 2-tailed P values are given below each correlation graph. (D) Schematic representation of naive Mo treatment with PA and increasing concentrations of glucose. (E) Scatter plot representation of RT-qPCR expression of selected markers in healthy donor naive Mos treated for 18 hours (or 42 hours for ANGPTL4) with either BSA (unbound BSA, blue dots) or PA (BSA-bound PA, red dots) and various concentrations of glucose. Values represent the mean ± SEM of 4 independent cultures. Statistical differences were analyzed by 2-way ANOVA interaction, and P values for the PA and glucose treatments are given below each graph.