Robo4‐mediated pancreatic endothelial integrity decreases inflammation and islet destruction in autoimmune diabetes
Robo4‐mediated pancreatic endothelial integrity decreases inflammation and islet destruction in autoimmune diabetes
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Robo4â 介导的胰腺内皮完整性可减少自身免疫性糖尿病中的炎症和胰岛破坏
DOI：
10.1096/fj.201900125rr
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Chatzigeorgiou A
中科院分区：
文献类型：
--
作者：
Troullinaki M;Chen LS;Witt A;Pyrina I;Phieler J;Kourtzelis I;Chmelar J;Sprott D;Gercken B;Koutsilieris M;Chavakis T;Chatzigeorgiou A
在1型糖尿病(T1 DM)中，在高血糖和临床疾病症状之前，胰岛的白细胞渗透和由此导致的免疫介导的β细胞破坏。在这种情况下，胰腺内皮细胞作为自身免疫和炎症相关的胰岛破坏屏障的作用还没有得到很好的研究。在这里，我们确定了表达于内皮细胞的Robo4是自身免疫性糖尿病期间胰腺血管内皮细胞通透性的调节因子。在多次小剂量链脲佐菌素(MLDS)糖尿病模型小鼠中，Robo4的循环水平被上调。在诱导MLDS时，Robo4缺乏导致胰腺血管通透性增加，胰岛白细胞浸润和胰岛细胞凋亡，与胰岛素水平降低和更快的糖尿病发展相关。相反，在小鼠体内应用Slit2适度推迟了MLDS诱导的糖尿病高血糖的出现，并减轻了胰岛炎症。因此，Robo4介导的内皮屏障完整性可以减少自身免疫性糖尿病患者的胰岛炎症和胰岛破坏。我们的发现强调了内皮细胞在T1 DM发展过程中作为胰腺炎症守门人的重要性，并可能为Robo4相关的自身免疫性糖尿病的新治疗方法铺平道路。
In Type 1 Diabetes Mellitus (T1DM), leukocyte infiltration of the pancreatic islets and the resulting immune‐mediated destruction of beta cells precede hyperglycemia and clinical disease symptoms. In this context, the role of the pancreatic endothelium as a barrier for autoimmunity‐ and inflammation‐related destruction of the islets is not well studied. Here, we identified Robo4, expressed on endothelial cells, as a regulator of pancreatic vascular endothelial permeability during autoimmune diabetes. Circulating levels of Robo4 were upregulated in mice subjected to the Multiple Low‐Dose Streptozotocin (MLDS) model of diabetes. Upon MLDS induction, Robo4‐deficiency resulted in increased pancreatic vascular permeability, leukocyte infiltration to the islets and islet apoptosis, associated with reduced insulin levels and faster diabetes development. On the contrary, in vivo administration of Slit2 in mice modestly delayed the emergence of hyperglycaemia and ameliorated islet inflammation in MLDS‐induced diabetes. Thus, Robo4‐mediated endothelial barrier integrity reduces insulitis and islet destruction in autoimmune diabetes. Our findings highlight the importance of the endothelium as gatekeeper of pancreatic inflammation during T1DM development and may pave the way for novel Robo4‐related therapeutic approaches for autoimmune diabetes.
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影响因子：
30.5
作者：
Chung KJ;Chatzigeorgiou A;Economopoulou M;Garcia-Martin R;Alexaki VI;Mitroulis I;Nati M;Gebler J;Ziemssen T;Goelz SE;Phieler J;Lim JH;Karalis KP;Papayannopoulou T;Blüher M;Hajishengallis G;Chavakis T
通讯作者：
Chavakis T
影响因子：
21.3
作者：
Jones CA;Nishiya N;London NR;Zhu W;Sorensen LK;Chan AC;Lim CJ;Chen H;Zhang Q;Schultz PG;Hayallah AM;Thomas KR;Famulok M;Zhang K;Ginsberg MH;Li DY
通讯作者：
Li DY
影响因子：
2.7
作者：
Park, KW;Morrison, CM;Li, DY
通讯作者：
Li, DY
影响因子：
5.3
作者：
García-Martín R;Alexaki VI;Qin N;Rubín de Celis MF;Economopoulou M;Ziogas A;Gercken B;Kotlabova K;Phieler J;Ehrhart-Bornstein M;Bornstein SR;Eisenhofer G;Breier G;Blüher M;Hampe J;El-Armouche A;Chatzigeorgiou A;Chung KJ;Chavakis T
通讯作者：
Chavakis T
影响因子：
20.1
作者：
Okada, Yoshiaki;Yano, Kiichiro;Aird, William C.
通讯作者：
Aird, William C.