Nigi Laura, Brusco Noemi, Grieco Giuseppina E, Licata Giada, Krogvold Lars, Marselli Lorella, Gysemans Conny, Overbergh Lut, Marchetti Piero, Mathieu Chantal, Dahl Jørgensen Knut, Sebastiani Guido, Dotta Francesco
Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.
Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy.
Front Endocrinol (Lausanne). 2020 Sep 15;11:630. doi: 10.3389/fendo.2020.00630. eCollection 2020.
C-X-C Motif Chemokine Ligand 10 (CXCL10) is a pro-inflammatory chemokine specifically recognized by the ligand receptor CXCR3 which is mostly expressed in T-lymphocytes. Although CXCL10 expression and secretion have been widely associated to pancreatic islets both in non-obese diabetic (NOD) mice and in human type 1 diabetic (T1D) donors, the specific expression pattern among pancreatic endocrine cell subtypes has not been clarified yet. Therefore, the purpose of this study was to shed light on the pancreatic islet expression of CXCL10 in NOD, in C57Bl/6J and in NOD-SCID mice as well as in human T1D pancreata from new-onset T1D patients (DiViD study) compared to non-diabetic multiorgan donors from the INNODIA European Network for Pancreatic Organ Donors with Diabetes (EUnPOD). CXCL10 was expressed in pancreatic islets of normoglycaemic and new-onset diabetic NOD mice but not in C57Bl/6J and NOD-SCID mice. CXCL10 expression was increased in pancreatic islets of new-onset diabetic NOD mice compared to normoglycaemic NOD mice. In NOD mice, CXCL10 colocalized both with insulin and glucagon. Interestingly, CXCL10-glucagon colocalization rate was significantly increased in diabetic vs. normoglycaemic NOD mouse islets, indicating an increased expression of CXCL10 also in alpha-cells. CXCL10 was expressed in pancreatic islets of T1D patients but not in non-diabetic donors. The analysis of the expression pattern of CXCL10 in human T1D pancreata from DiViD study, revealed an increased colocalization rate with glucagon compared to insulin. Of note, CXCL10 was also expressed in alpha-cells residing in insulin-deficient islets (IDI), suggesting that CXCL10 expression in alpha cells is not driven by residual beta-cells and therefore may represent an independent phenomenon. In conclusion, we show that in T1D CXCL10 is expressed by alpha-cells both in NOD mice and in T1D patients, thus pointing to an additional novel role for alpha-cells in T1D pathogenesis and progression.
C-X-C基序趋化因子配体10（CXCL10）是一种促炎趋化因子，可被主要在T淋巴细胞中表达的配体受体CXCR3特异性识别。尽管在非肥胖糖尿病（NOD）小鼠和人类1型糖尿病（T1D）供体中，CXCL10的表达和分泌都与胰岛广泛相关，但胰腺内分泌细胞亚型中的具体表达模式尚未明确。因此，本研究的目的是阐明NOD、C57Bl/6J和NOD-SCID小鼠以及新发T1D患者的人类T1D胰腺中CXCL10在胰岛中的表达情况（DiViD研究），并与来自欧洲糖尿病胰腺器官捐赠者网络（EUnPOD）的非糖尿病多器官捐赠者进行比较。CXCL10在血糖正常和新发糖尿病的NOD小鼠胰岛中表达，但在C57Bl/6J和NOD-SCID小鼠中不表达。与血糖正常的NOD小鼠相比，新发糖尿病NOD小鼠胰岛中CXCL10的表达增加。在NOD小鼠中，CXCL10与胰岛素和胰高血糖素均共定位。有趣的是，糖尿病NOD小鼠胰岛中CXCL10与胰高血糖素的共定位率显著高于血糖正常的NOD小鼠胰岛，表明α细胞中CXCL10的表达也增加。CXCL10在T1D患者的胰岛中表达，但在非糖尿病供体中不表达。对DiViD研究中人类T1D胰腺中CXCL10表达模式的分析显示，与胰岛素相比，其与胰高血糖素的共定位率增加。值得注意的是，CXCL10也在胰岛素缺乏胰岛（IDI）中的α细胞中表达，这表明α细胞中CXCL10的表达不是由残余β细胞驱动的，因此可能是一种独立现象。总之，我们表明在T1D中，CXCL10在NOD小鼠和T1D患者的α细胞中均有表达，从而指出α细胞在T1D发病机制和进展中的另一个新作用。
