Pancreatic Alpha-Cells Contribute Together With Beta-Cells to CXCL10 Expression in Type 1 Diabetes

Abstract

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.

Increased expression of viral sensor MDA5 in pancreatic islets and in hormone-negative endocrine cells in recent onset type 1 diabetic donors

“…The increased colocalization rate between MDA5-glucagon and MDA5-insulin in T1D cases, possibly reflects ongoing inflammation of pancreatic islets particularly in recent onset cases. Of note, the strongest MDA5 increase was observed in β-cells of T1D DiViD case-3 which, among T1D DiViD donors, previously showed high level of insulitis alongside with a strong expression of HLA class-I molecules and several specific cytokines and chemokines (30,34,35). These results are in line with in-vitro studies showing that increased expression of MDA5 is also driven by pro-inflammatory molecules.…”

“…The colocalization rate of MDA5-glucagon and MDA5-insulin in non-diabetic controls was highly heterogenous both among islets of the same donor and among different donors; nevertheless the overall result showed a significant preferential localization in α-cells. Such heterogeneity was expected, based on previous findings on other molecules (30,31) and on other reports (32,33).…”

New Insights Into the Role of Autoreactive CD8 T Cells and Cytokines in Human Type 1 Diabetes

“…More recently, Nigi et al have shown CXCL10 expression in alpha cells and beta cells of donors with T1D. Interestingly, insulin-containing islets in T1D had an increased percentage of CXCL10-positive alpha cells compared to CXCL-10-positive beta cells suggesting an involvement of alpha cells in chemokine secretion (38). Both CXCL9 and CXCL10 have been shown to be secreted by beta cells in insulitic islets, which drive CXCR3+ autoreactive T cells to islets in the RIP-LCMV model of T1D.…”

Partners in Crime: Beta-Cells and Autoimmune Responses Complicit in Type 1 Diabetes Pathogenesis

“…C-X-C motif chemokine ligand 10 (CXCL10) also called IP-10 (IFNg-induced protein 10) is a chemokine secreted by many cell types including monocytes, neutrophils, and endothelial cells (130,131). CXCL10 is increased in the serum and tissues of patients with various autoimmune diseases including T1D (99,132). Human islets, murine islets, and NIT-1 NOD beta-cells secrete CXCL10 when cultured with pro-inflammatory cytokines IL-1b and IFNg (127).…”