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Patrolling Monocytes Are Recruited and Activated by Diabetes to Protect Retinal Microvessels
Francesco Tecilazich1,2,3, Toan A Phan4, Fabio Simeoni5
1Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA francescotecilazich@gmail.com.
Abstract:
In diabetes there is a long latency between the onset of hyperglycemia and the 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 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.
Insights
In diabetes, patrolling monocytes (PMo) protect retinal vessels from damage. Their absence in diabetic mice leads to increased microvascular damage, suggesting a protective role for PMo in diabetic retinopathy.
Area of Science:
- Vascular biology
- Immunology
- Diabetic complications
Background:
- Diabetes is characterized by a significant delay between hyperglycemia onset and microangiopathy.
- Ly6C low patrolling monocytes (PMo) are known to maintain vascular health.
- The role of PMo in the early stages of diabetic microvascular complications remains unclear.
Purpose of the Study:
- To investigate the protective role of patrolling monocytes (PMo) in preventing microvascular damage in early diabetes.
- To determine if PMo recruitment to retinal vessels mitigates diabetic microangiopathy.
Main Methods:
- Comparison of wild-type and NR4A1-/- mice (lacking PMo) under diabetic conditions.
- Quantification of PMo in circulation and adherence to retinal vessels (leukostasis).
- Assessment of retinal acellular capillaries as a marker of microvascular damage.
- Analysis of gene expression in circulating PMo.
Main Results:
- Diabetes reduced circulating PMo but increased their adherence to retinal vessels in wild-type mice.
- Diabetic NR4A1-/- mice showed no increase in leukostasis and a significant rise in retinal acellular capillaries.
- Circulating PMo exhibited gene expression changes supporting migratory, vasculoprotective, and housekeeping functions, with suppressed inflammation and apoptosis.
- Upregulation of promigratory CXCR4 diminished with longer diabetes duration, coinciding with increased acellular capillaries.
Conclusions:
- Patrolling monocytes (PMo) are preferentially recruited to retinal vessels early in diabetes and exert a protective effect against microvascular damage.
- The findings necessitate a re-evaluation of leukostasis in diabetes, highlighting protective and reparative mechanisms in diabetic retinopathy.
- PMo represent a potential therapeutic target for preventing or mitigating diabetic retinopathy progression.
