FRANCESCO_TECILAZICH-PMo_Paper_DIABETES_REVISION_SUPPLEM-_FINAL.pdf (480.68 kB)

Patrolling monocytes are recruited and activated by diabetes to protect retinal microvessels

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posted on 10.09.2020 by Ada Admin, Francesco Tecilazich, Toan A. Phan, Fabio Simeoni, Giulia Maria Scotti, Zeina Dagher, Mara Lorenzi
In diabetes there is a long latency between onset of hyperglycemia and appearance of structural microangiopathy. Because Ly6Clow 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 4-fold 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 at all; and at 6 months of diabetes the number of retinal acellular capillaries almost doubled when compared to diabetic wild-type mice. Circulating PMo showed gene expression changes indicative of enhanced migratory, vasculo-protective, and housekeeping activities; as well as profound suppression of genes related to inflammation and apoptosis. Pro-migratory CXCR4 was no longer upregulated at longer duration, when retinal acellular capillaries begin to increase.

Thus, after 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-repair that can provide novel paradigms for prevention.

Funding

This work was supported by the NIH (R21 EY024108 to M. Lorenzi); the Global Ophthalmology Award Program from Bayer to M. Lorenzi; the European Foundation for the Study of Diabetes (EFSD)/Boehringer Ingelheim European Research Programme in Microvascular Complications of Diabetes to F. Tecilazich and G. Zerbini; the Marie Skłodowska-Curie Actions 795877 to F. Tecilazich; the NIH National Eye Institute Core Grant P30EY003790; and the Italian Ministry of Health (5 x 1000).

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