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

Autor: Blot G; Institute of Vision, Sorbonne University, INSERM, CNRS, Paris, France.; ED394 Physiology and Physiopathology Doctoral School, Sorbonne University, Paris, France., Karadayi R; Institute of Vision, Sorbonne University, INSERM, CNRS, Paris, France., Przegralek L; Institute of Vision, Sorbonne University, INSERM, CNRS, Paris, France., Sartoris TM; Institute of Vision, Sorbonne University, INSERM, CNRS, Paris, France., Charles-Messance H; Institute of Vision, Sorbonne University, INSERM, CNRS, Paris, France.; ED394 Physiology and Physiopathology Doctoral School, Sorbonne University, Paris, France., Augustin S; Institute of Vision, Sorbonne University, INSERM, CNRS, Paris, France., Negrier P; Institute of Vision, Sorbonne University, INSERM, CNRS, Paris, France.; A. de Rothschild Foundation Hospital, Paris, France., Blond F; Institute of Vision, Sorbonne University, INSERM, CNRS, Paris, France., Muñiz-Ruvalcaba FP; Institute of Vision, Sorbonne University, INSERM, CNRS, Paris, France., Rivera-de la Parra D; Comprehensive Care Center for Diabetes Patients, Salvador Zubrian National Institute of Health Sciences and Nutrition, Mexico City, Mexico.; Institute of Ophthalmology 'Fundación Conde de Valenciana' I.A.P., Mexico City, Mexico., Vignaud L; Institute of Vision, Sorbonne University, INSERM, CNRS, Paris, France., Couturier A; Institute of Vision, Sorbonne University, INSERM, CNRS, Paris, France.; ED394 Physiology and Physiopathology Doctoral School, Sorbonne University, Paris, France.; Department of Ophthalmology, Hôpital Lariboisière, AP-HP, University of Paris, Paris, France., Sahel JA; Institute of Vision, Sorbonne University, INSERM, CNRS, Paris, France.; A. de Rothschild Foundation Hospital, Paris, France.; Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; CHNO des Quinze-Vingts, Institut Hospitalo-Universitaire FOReSIGHT, INSERM-DGOS CIC 1423, Paris, France., Acar N; Eye and Nutrition Research Group, Center for Taste and Food Sciences, CNRS, INRAE, Institut Agro, Bourgogne Franche-Comté University, Dijon, France., Jimenez-Corona A; Department of Epidemiology and Visual Health, Instituto de Oftalmología Fundación Conde de Valenciana, Mexico City, Mexico.; General Directorate of Epidemiology, Secretariat of Health, Mexico City, Mexico., Delarasse C; Institute of Vision, Sorbonne University, INSERM, CNRS, Paris, France., Garfias Y; Department of Biochemistry, School of Medicine, National Autonomous University, Mexico City, Mexico.; Cell and Tissue Biology, Research Unit, Instituto de Oftalmología Fundación Conde de Valenciana', Mexico City, Mexico., Sennlaub F; Institute of Vision, Sorbonne University, INSERM, CNRS, Paris, France., Guillonneau X; Institute of Vision, Sorbonne University, INSERM, CNRS, Paris, France.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2023 Oct 02; Vol. 133 (19). Date of Electronic Publication: 2023 Oct 02.
DOI: 10.1172/JCI161348
Abstrakt: 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.
Databáze: MEDLINE