CCR2-positive monocytes contribute to the pathogenesis of early diabetic retinopathy in mice.
CCR2-positive monocytes contribute to the pathogenesis of early diabetic retinopathy in mice.
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DOI：
10.1007/s00125-022-05860-w
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发表时间：
2023-03
期刊：
影响因子：
8.2
通讯作者：
Kern, Timothy S.
中科院分区：
文献类型：
--
作者：
Saadane, Aicha;Veenstra, Alexander A.;Minns, Martin S.;Tang, Jie;Du, Yunpeng;Elghazali, Fatima Abubakr;Lessieur, Emma M.;Pearlman, Eric;Kern, Timothy S.
越来越多的证据表明，白细胞在糖尿病引起的血管病变和其他异常中起着关键作用，这些异常导致早期糖尿病视网膜病变。然而，单核细胞的作用尚未得到充分研究;因此，我们使用Ccr 2 −/−小鼠研究CCR 2+炎性单核细胞在糖尿病诱导的视网膜毛细血管变性发病机制中的作用。使用链脲佐菌素在野生型和Ccr 2 −/−小鼠中诱导实验性糖尿病。2个月后，评价超氧化物水平、炎症基因表达、白细胞停滞、白细胞和单核细胞介导的抗视网膜内皮细胞死亡的细胞毒性、视网膜厚度和视功能。糖尿病8个月后测定视网膜毛细血管变性。采用流式细胞术检测外周血单核细胞中CCR 2的差异表达。在非糖尿病小鼠中，CCR 2在单核细胞上高度表达，而Ccr 2 −/−小鼠外周血中缺乏CCR 2+单核细胞。糖尿病诱导的视网膜超氧化物，促炎基因Inos和Icam 1的表达，白细胞停滞和白细胞介导的对视网膜内皮细胞的细胞毒性被抑制在糖尿病Ccr 2缺陷小鼠和嵌合体小鼠缺乏Ccr 2只从骨髓细胞。为了关注单核细胞，在糖尿病2个月后免疫分离这些细胞，并且它们显著增加单核细胞介导的内皮细胞离体细胞毒性。Ccr 2缺陷小鼠的单核细胞引起的内皮细胞死亡显著减少。糖尿病诱导的视网膜毛细血管变性在Ccr 2 −/−小鼠和仅从骨髓细胞缺乏Ccr 2的嵌合小鼠中得到抑制。CCR 2+炎性单核细胞参与了糖尿病视网膜病变早期病变的发病机制。在线版本包含同行评审但未经编辑的补充材料，可通过10.1007/s 00125 -022-05860-w获得。
Accumulating evidence suggests that leucocytes play a critical role in diabetes-induced vascular lesions and other abnormalities that characterise the early stages of diabetic retinopathy. However, the role of monocytes has yet to be fully investigated; therefore, we used Ccr2−/− mice to study the role of CCR2+ inflammatory monocytes in the pathogenesis of diabetes-induced degeneration of retinal capillaries. Experimental diabetes was induced in wild-type and Ccr2−/− mice using streptozotocin. After 2 months, superoxide levels, expression of inflammatory genes, leucostasis, leucocyte- and monocyte-mediated cytotoxicity against retinal endothelial cell death, retinal thickness and visual function were evaluated. Retinal capillary degeneration was determined after 8 months of diabetes. Flow cytometry of peripheral blood for differential expression of CCR2 in monocytes was assessed. In nondiabetic mice, CCR2 was highly expressed on monocytes, and Ccr2−/− mice lack CCR2+ monocytes in the peripheral blood. Diabetes-induced retinal superoxide, expression of proinflammatory genes Inos and Icam1, leucostasis and leucocyte-mediated cytotoxicity against retinal endothelial cells were inhibited in diabetic Ccr2-deficient mice and in chimeric mice lacking Ccr2 only from myeloid cells. In order to focus on monocytes, these cells were immuno-isolated after 2 months of diabetes, and they significantly increased monocyte-mediated endothelial cell cytotoxicity ex vivo. Monocytes from Ccr2-deficient mice caused significantly less endothelial cell death. The diabetes-induced retinal capillary degeneration was inhibited in Ccr2−/− mice and in chimeric mice lacking Ccr2 only from myeloid cells. CCR2+ inflammatory monocytes contribute to the pathogenesis of early lesions of diabetic retinopathy. The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-022-05860-w.
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影响因子：
7.7
作者：
Asnaghi, V;Gerhardinger, C;Lorenzi, M
通讯作者：
Lorenzi, M
影响因子：
4.8
作者：
Du，Yunpeng;Cramer，Megan;Kern，Timothy S.
通讯作者：
Kern，Timothy S.
影响因子：
4.4
作者：
Feit-Leichman, RA;Kinouchi, R;Chen, DF
通讯作者：
Chen, DF
DOI：
10.1073/pnas.1314575110
发表时间：
2013-10-08
影响因子：
11.1
作者：
Du, Yunpeng;Veenstra, Alexander;Kern, Timothy S.
通讯作者：
Kern, Timothy S.
影响因子：
5.3
作者：
Evans, Teresa A.;Barkauskas, Deborah S.;Myers, Jay T.;Hare, Elisabeth G.;You, Jing Qiang;Ransohoff, Richard M.;Huang, Alex Y.;Silver, Jerry
通讯作者：
Silver, Jerry