TY - JOUR
T1 - Patrolling monocytes are recruited and activated by diabetes to protect retinal microvessels
AU - Tecilazich, Francesco
AU - Phan, Toan A.
AU - Simeoni, Fabio
AU - Scotti, Giulia Maria
AU - Dagher, Zeina
AU - Lorenzi, Mara
N1 - Funding Information:
The authors are grateful to Dr. C. Gerhardinger (Harvard Department of Stem Cell and Regenerative Biology) for her advice and assistance with RNA experiments, Dr. R. Nayar (Center for Systems Biology at Massachusetts General Hospital and Harvard Medical School) for her advice in planning the RNA-Seq procedure, and Dr. G. Zerbini and Prof. A. Giustina for continuous interest and encouragement. Funding and Duality of Interest. This work was supported by the European Foundation for the Study of Diabetes (EFSD)/Boehringer Ingelheim European Research Programme in Microvascular Complications of Diabetes to F.T., the European Union?s Horizon 2020 research and innovation programme under the Marie Sk?odowska-Curie grant agreement No. 795877 to F.T., the Global Ophthalmology Award Program from Bayer to M.L., and National Institutes of Health National Eye Institute (grant R21 EY024108 to M.L.) and the core grant P30EY003790, and the Italian Ministry of Health (5?1,000). No other potential conflicts of interest relevant to this article were reported.
Funding Information:
Acknowledgments. The authors are grateful to Dr. C. Gerhardinger (Harvard Department of Stem Cell and Regenerative Biology) for her advice and assistance with RNA experiments, Dr. R. Nayar (Center for Systems Biology at Massachusetts General Hospital and Harvard Medical School) for her advice in planning the RNA-Seq procedure, and Dr. G. Zerbini and Prof. A. Giustina for continuous interest and encouragement. Funding and Duality of Interest. This work was supported by the European Foundation for the Study of Diabetes (EFSD)/Boehringer Ingelheim European Research Programme in Microvascular Complications of Diabetes to F.T., the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 795877 to F.T., the Global Ophthalmology Award Program from Bayer to M.L., and National Institutes of Health National Eye Institute (grant R21 EY024108 to M.L.) and the core grant P30EY003790, and the Italian Ministry of Health (5⨯1,000). No other potential conflicts of interest relevant to this article were reported. Author Contributions. F.T. and T.A.P. maintained the mouse colony, induced and managed diabetes in mice, and performed the flow cytometry and intracardiac perfusion experiments. F.T., T.A.P., and Z.D. performed the immunofluorescence experiments, trypsin digestions, and the counts of acellular capillaries. F.T. and M.L. designed the study, analyzed the data, and wrote the article. F.S. performed the real-time qPCR experiments. G.M.S. performed the bioinformatic analysis. F.T. and M.L. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Publisher Copyright:
© 2020 by the American Diabetes Association.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12
Y1 - 2020/12
N2 - In diabetes there is a long latency between the onset of hyperglycemia and the appearance of structural micro-angiopathy. 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, vasculopro-tective, and housekeeping activities, as well as profound suppression of genes related to inflammation and apo-ptosis. 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 pro-cesses of protection and repair that can provide novel paradigms for prevention.
AB - In diabetes there is a long latency between the onset of hyperglycemia and the appearance of structural micro-angiopathy. 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, vasculopro-tective, and housekeeping activities, as well as profound suppression of genes related to inflammation and apo-ptosis. 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 pro-cesses of protection and repair that can provide novel paradigms for prevention.
UR - http://www.scopus.com/inward/record.url?scp=85096594050&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85096594050&partnerID=8YFLogxK
U2 - 10.2337/db19-1043
DO - 10.2337/db19-1043
M3 - Article
C2 - 32907815
AN - SCOPUS:85096594050
VL - 69
SP - 2709
EP - 2719
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 12
ER -