Patrolling Monocytes Are Recruited and Activated by Diabetes to Protect Retinal Microvessels

Overview

Journal Diabetes

Specialty Endocrinology

Date 2020 Sep 10

PMID 32907815

Citations 6

Authors

Francesco Tecilazich

Toan A Phan

Fabio Simeoni

Giulia Maria Scotti

Zeina Dagher

Mara Lorenzi

Affiliations

Soon will be listed here.

Abstract

In diabetes there is a long latency between the onset of hyperglycemia and the appearance of structural microangiopathy. Because Ly6C patrolling monocytes (PMo) behave as housekeepers of the vasculature, we tested whether PMo protect microvessels against diabetes. We found that in wild-type mice, diabetes reduced PMo in the general circulation but increased by fourfold the absolute number of PMo adherent to retinal vessels (leukostasis). Conversely, in diabetic NR4A1 mice, a model of absence of PMo, there was no increase in leukostasis, and at 6 months of diabetes, the number of retinal acellular capillaries almost doubled compared with diabetic wild-type mice. Circulating PMo showed gene expression changes indicative of enhanced migratory, vasculoprotective, and housekeeping activities, as well as profound suppression of genes related to inflammation and apoptosis. Promigratory CXCR4 was no longer upregulated at longer duration when retinal acellular capillaries begin to increase. Thus, after a short diabetes duration, PMo are the cells preferentially recruited to the retinal vessels and protect vessels from diabetic damage. These observations support the need for reinterpretation of the functional meaning of leukostasis in diabetes and document within the natural history of diabetic retinopathy processes of protection and repair that can provide novel paradigms for prevention.

Citing Articles

Monocytes in Retinal Degeneration: Little Cells with a Big Impact.

Ronning K, Burns M, Sennlaub F Adv Exp Med Biol. 2025; 1468:133-137.

PMID: 39930185 DOI: 10.1007/978-3-031-76550-6_22.

Association between macrophage-like cell density and ischemia metrics in diabetic eyes.

Bisen J, Heisel C, Duffy B, Decker N, Fukuyama H, Boughanem G Exp Eye Res. 2024; 237:109703.

PMID: 38652673 PMC: 11040107. DOI: 10.1016/j.exer.2023.109703.

Macrophage activation contributes to diabetic retinopathy.

Zhang Y, Zhou A J Mol Med (Berl). 2024; 102(5):585-597.

PMID: 38429382 DOI: 10.1007/s00109-024-02437-5.

NR4A1 deletion promotes pro-angiogenic polarization of macrophages derived from classical monocytes in a mouse model of neovascular age-related macular degeneration.

Droho S, Voigt A, Sterling J, Rajesh A, Chan K, Cuda C J Neuroinflammation. 2023; 20(1):238.

PMID: 37858232 PMC: 10588116. DOI: 10.1186/s12974-023-02928-1.

Macrophages in close proximity to the vitreoretinal interface are potential biomarkers of inflammation during retinal vascular disease.

Rajesh A, Droho S, Lavine J J Neuroinflammation. 2022; 19(1):203.

PMID: 35941655 PMC: 9361599. DOI: 10.1186/s12974-022-02562-3.

References

McVicar C, Ward M, Colhoun L, Guduric-Fuchs J, Bierhaus A, Fleming T . Role of the receptor for advanced glycation endproducts (RAGE) in retinal vasodegenerative pathology during diabetes in mice. Diabetologia. 2015; 58(5):1129-37. PMC: 4392170. DOI: 10.1007/s00125-015-3523-x. View

Kraakman M, Murphy A, Jandeleit-Dahm K, Kammoun H . Macrophage polarization in obesity and type 2 diabetes: weighing down our understanding of macrophage function?. Front Immunol. 2014; 5:470. PMC: 4176397. DOI: 10.3389/fimmu.2014.00470. View

Zhang J, Gerhardinger C, Lorenzi M . Early complement activation and decreased levels of glycosylphosphatidylinositol-anchored complement inhibitors in human and experimental diabetic retinopathy. Diabetes. 2002; 51(12):3499-504. DOI: 10.2337/diabetes.51.12.3499. View

Mizutani M, Kern T, Lorenzi M . Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. J Clin Invest. 1996; 97(12):2883-90. PMC: 507384. DOI: 10.1172/JCI118746. View

Abiko T, Abiko A, Clermont A, Shoelson B, Horio N, Takahashi J . Characterization of retinal leukostasis and hemodynamics in insulin resistance and diabetes: role of oxidants and protein kinase-C activation. Diabetes. 2003; 52(3):829-37. DOI: 10.2337/diabetes.52.3.829. View

Yamagishi S, Matsui T, Nakamura K, Takeuchi M, Imaizumi T . Pigment epithelium-derived factor (PEDF) prevents diabetes- or advanced glycation end products (AGE)-elicited retinal leukostasis. Microvasc Res. 2006; 72(1-2):86-90. DOI: 10.1016/j.mvr.2006.04.002. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Nimmerjahn F, Bruhns P, Horiuchi K, Ravetch J . FcgammaRIV: a novel FcR with distinct IgG subclass specificity. Immunity. 2005; 23(1):41-51. DOI: 10.1016/j.immuni.2005.05.010. View

Dagher Z, Park Y, Asnaghi V, Hoehn T, Gerhardinger C, Lorenzi M . Studies of rat and human retinas predict a role for the polyol pathway in human diabetic retinopathy. Diabetes. 2004; 53(9):2404-11. DOI: 10.2337/diabetes.53.9.2404. View

10.

Zerbini G, Maestroni A, Palini A, Tremolada G, Lattanzio R, Maestroni S . Endothelial progenitor cells carrying monocyte markers are selectively abnormal in type 1 diabetic patients with early retinopathy. Diabetes. 2012; 61(4):908-14. PMC: 3314367. DOI: 10.2337/db11-1197. View

11.

Kinoshita N, Kakehashi A, Inoda S, Itou Y, Kuroki M, Yasu T . Effective and selective prevention of retinal leukostasis in streptozotocin-induced diabetic rats using gliclazide. Diabetologia. 2002; 45(5):735-9. DOI: 10.1007/s00125-002-0820-y. View

12.

Gerhardinger C, McClure K, Romeo G, Podesta F, Lorenzi M . IGF-I mRNA and signaling in the diabetic retina. Diabetes. 2001; 50(1):175-83. DOI: 10.2337/diabetes.50.1.175. View

13.

Gerhardinger C, Dagher Z, Sebastiani P, Park Y, Lorenzi M . The transforming growth factor-beta pathway is a common target of drugs that prevent experimental diabetic retinopathy. Diabetes. 2009; 58(7):1659-67. PMC: 2699853. DOI: 10.2337/db08-1008. View

14.

Hanna R, Cekic C, Sag D, Tacke R, Thomas G, Nowyhed H . Patrolling monocytes control tumor metastasis to the lung. Science. 2015; 350(6263):985-90. PMC: 4869713. DOI: 10.1126/science.aac9407. View

15.

Dagher Z, Gerhardinger C, Vaz J, Goodridge M, Tecilazich F, Lorenzi M . The Increased Transforming Growth Factor-β Signaling Induced by Diabetes Protects Retinal Vessels. Am J Pathol. 2017; 187(3):627-638. PMC: 5397667. DOI: 10.1016/j.ajpath.2016.11.007. View

16.

Jung K, Heishi T, Khan O, Kowalski P, Incio J, Rahbari N . Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy. J Clin Invest. 2017; 127(8):3039-3051. PMC: 5531423. DOI: 10.1172/JCI93182. View

17.

Jung K, Heishi T, Incio J, Huang Y, Beech E, Pinter M . Targeting CXCR4-dependent immunosuppressive Ly6C monocytes improves antiangiogenic therapy in colorectal cancer. Proc Natl Acad Sci U S A. 2017; 114(39):10455-10460. PMC: 5625928. DOI: 10.1073/pnas.1710754114. View

18.

Hanna R, Carlin L, Hubbeling H, Nackiewicz D, Green A, Punt J . The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes. Nat Immunol. 2011; 12(8):778-85. PMC: 3324395. DOI: 10.1038/ni.2063. View

19.

Tamura H, Miyamoto K, Kiryu J, Miyahara S, Katsuta H, Hirose F . Intravitreal injection of corticosteroid attenuates leukostasis and vascular leakage in experimental diabetic retina. Invest Ophthalmol Vis Sci. 2005; 46(4):1440-4. DOI: 10.1167/iovs.04-0905. View

20.

Belia S, Santilli F, Beccafico S, De Feudis L, Morabito C, Davi G . Oxidative-induced membrane damage in diabetes lymphocytes: effects on intracellular Ca(2 +) homeostasis. Free Radic Res. 2008; 43(2):138-48. DOI: 10.1080/10715760802629588. View