Increased Circulating Levels of CXC Chemokines is Correlated with Duration and Complications of the Disease in Type-1 Diabetes: A Study on Iranian Diabetic Patients

Abstract

Background: Type-1 diabetes (T1D) is characterized as a heterogenous autoimmune disease. Immune system factors are important in the pathogenesis of T1D. Chemokines as crucial members of the immune system are key factors in the pathogenesis of several autoimmune diseases, including T1D. They are potent chemotactic cytokines with various functions varied from maturation, trafficking of leukocytes, to angiogenesis, angiostasis, and homing of stem cells. Therefore, the current study was aimed to examine if the expression of pro-angiogenic CXC chemokines like CXCL1 and anti-angiogenic chemochines such as CXCL9 are associated with duration and complications of T1D in Iranian diabetic patients. Methods: In this experimental study, blood samples were collected from 209 T1D patients and 189 healthy controls. The serum levels of CXCL1 and CXCL9 were measured by ELISA. Demographic data were also collected on a questionnaire which was designed specifically for this study. Results: Increased plasma levels of chemokines studied (CXCL1 and CXCL9) were observed in T1D patients compared to controls. Current findings also demonstrated that there was a close association between chemokines and complications of T1D and chemokines were elevated in T1D patients suffering complications. Conclusions: Our results probably suggest that the serum levels of CXCL1 and CXCL9 play important roles in T1D pathogenesis. It is also worth noting that these factors are useful prognostic and/or diagnostic biological markers in T1D patients.

CXCR1/2 Inhibition Blocks and Reverses Type 1 Diabetes in Mice

“…Human pancreatic islets produce and secrete the proinflammatory CXCL8 and CXCL1 ligands (12,15,17,22,23), whereas lipopolysaccharide-induced production of CXCL8 by neutrophils is increased in prediabetic and T1D patients. In parallel, circulating concentrations of CXCL8 are elevated in children with T1D compared with nondiabetic controls (24)(25)(26). Specifically, concentrations of CXCL8 correlate with glycemic control; higher concentrations are associated with poor or inadequate glucose control.…”

“…In fact, pancreatic islets produce and secrete the CXCR1/2 chemokine ligands (named CXCL8, CXCL1, and CXCL2) in response to proinflammatory cytokines (12,15,17,22,23). Furthermore, the concentration of CXCR1/2 ligands is elevated in the blood of both rodents and humans with autoimmune diabetes (24)(25)(26); most important, recent reports support the notion that neutrophils (the major target of CXCR1/2 inhibitors) play a key role in the etiopathogenesis of T1D (27)(28)(29). We therefore extensively characterized the consequences of CXCR1/2 inhibition on inflammation-and autoimmunity-mediated diabetes in preclinical models.…”

Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes

“…CXCL1 is expressed by macrophages, neutrophils, and epithelial cells and has neutrophil chemoattractant activity. Interestingly, increased plasma CXCL1 was observed in T1D patients (21). Moreover, during inflammation, pancreatic macrophages and ␤-cells produce this chemokine, recruiting leucocytes from blood to the islets (10).…”

“…2A), and IMT504 treatment, or saline as control, was commenced (day 1). Blood glucose increased progressively in STZ-saline mice during 10 wk of evaluation, whereas it decreased significantly in STZ-IMT504 mice (repeated-measures 2-way ANOVA, interaction P Ͻ 0.001, STZ-IMT504 different from STZ-saline on days 6,11,21,26,29,32,36,41,46,53, and 66, P Ͻ 0.01 or less; Fig. 2A).…”

“…of doses : 20). Glycemia was measured in tail blood samples in nonfasted conditions on days 1,6,11,17,21,26,29,32,36,41,46,53, and 66 at 11-12 AM (last IMT504 injection on day 40). Intraperitoneal glucose tolerance tests (IPGTT) were performed on day 60.…”