The DNA Sensor AIM2 Protects against Streptozotocin-Induced Type 1 Diabetes by Regulating Intestinal Homeostasis via the IL-18 Pathway
Open Access
- 14 April 2020
- Vol. 9 (4), 959
- https://doi.org/10.3390/cells9040959
Abstract
Pattern recognition receptors (PRRs), such as Nod2, Nlrp3, Tlr2, Trl4, and Tlr9, are directly involved in type 1 diabetes (T1D) susceptibility. However, the role of the cytosolic DNA sensor, AIM2, in T1D pathogenesis is still unknown. Here, we demonstrate that C57BL/6 mice lacking AIM2 (AIM2−/−) are prone to streptozotocin (STZ)-induced T1D, compared to WT C57BL/6 mice. The AIM2−/− mice phenotype is associated with a greater proinflammatory response in pancreatic tissues, alterations in gut microbiota and bacterial translocation to pancreatic lymph nodes (PLNs). These alterations are related to an increased intestinal permeability mediated by tight-junction disruption. Notably, AIM2−/− mice treated with broad-spectrum antibiotics (ABX) are protected from STZ-induced T1D and display a lower pancreatic proinflammatory response. Mechanistically, the AIM2 inflammasome is activated in vivo, leading to an IL-18 release in the ileum at 15 days after an STZ injection. IL-18 favors RegIIIγ production, thus mitigating gut microbiota alterations and reinforcing the intestinal barrier function. Together, our findings show a regulatory role of AIM2, mediated by IL-18, in shaping gut microbiota and reducing bacterial translocation and proinflammatory response against insulin-producing β cells, which ultimately results in protection against T1D onset in an STZ-induced diabetes model.This publication has 55 references indexed in Scilit:
- Environmental Risk Factors for Type 1 Diabetes Mellitus DevelopmentExperimental and Clinical Endocrinology & Diabetes, 2017
- Environmental risk factors for type 1 diabetesThe Lancet, 2016
- Does the gut microbiota have a role in type 1 diabetes? Early evidence from humans and animal models of the diseaseDiabetologia, 2012
- Gut Microbiota and Type 1 DiabetesThe Review of Diabetic Studies, 2012
- Animal models of diabetes mellitusDiabetic Medicine, 2005
- β-Cell death during progression to diabetesNature, 2001
- Effect of Modified Diabetic Splenocytes on Mice Injected with Splenocytes from Multiple Low-Dose Streptozotocin Diabetic DonorsExperimental Biology and Medicine, 2001
- Birth weight and childhood onset type 1 diabetes: population based cohort studyBMJ, 2001
- Autoimmune Diabetes Induced by the β-cell Toxin STZ: Immunity to the 60-kDa Heat Shock Protein and to InsulinDiabetes, 1994
- Insulin-dependent diabetes mellitus induced by subdiabetogenic doses of streptozotocin: obligatory role of cell-mediated autoimmune processes.Proceedings of the National Academy of Sciences of the United States of America, 1980