The DNA Sensor AIM2 Protects against Streptozotocin-Induced Type 1 Diabetes by Regulating Intestinal Homeostasis via the IL-18 Pathway

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.

NLR and Intestinal Dysbiosis-Associated Inflammatory Illness: Drivers or Dampers?

“…The effects induced by AIM2 activation in vivo are mediated by IL-18 release, which favors regenerating islet-derived III gamma (RegIIIγ) production, thus mitigating gut microbiota alterations and reinforcing the intestinal barrier function. Together, our data show that AIM2 activation limits gut microbiota dysbiosis, intestinal permeability and translocation to PLNs, decreasing a proinflammatory response, and conferring protection against T1D ( 90 ).…”

“…data show that AIM2 activation limits gut microbiota dysbiosis, intestinal permeability and translocation to PLNs, decreasing a proinflammatory response, and conferring protection against T1D (90).…”

Premature Activation of Immune Transcription Programs in Autoimmune-Predisposed Mouse Embryonic Stem Cells and Blastocysts

“…On the contrary, Aim2 was found to be down-regulated in NOD compared to B6 ES cells, and was previously shown to be protective for B6 mice from developing diabetes in the presence of Steptozotocin [43], supporting the gene expression profiles predisposing to diabetes in NOD mice. Interestingly, diabetes-resistant B6 ES cells differentially overexpressed other immune-related genes, while a different set of immune-related genes was expressed at equal levels in both ES cells.…”

Inflammasomes and Type 1 Diabetes

“…To date, only two inflammasome-associated proteins (NLRP3 and AIM2) have been studied for their role in modulating susceptibility to T1D using gene-deficient mice ( 34 , 54 , 55 ). NLRP3-deficient NOD mice were protected from the development of T1D compared to wild-type littermates, as were wild-type NOD mice treated with an NLRP3 inhibitor (parthenolide; 10mg/kg body weight, twice a week for 4 weeks from 10-12 weeks of age) ( 54 ).…”

“…These findings were similar to those from the STZ-induced NOD2-deficient mouse study ( 126 ), with the inference that NOD2 activation of inflammasomes may be ASC-dependent. In humans, Aim2 gene expression was increased in the pancreas but not in peripheral blood mononuclear cells (PBMCs) in individuals with T1D compared to healthy controls ( 55 ); however, the data from the pancreas was only available in a small group (n=4-8) and thus needs to be confirmed in larger cohorts, ideally separating infiltrating immune cells from the islet β-cells. Another study in humans found that NLRP1 and NLRP3 gene expression was reduced in PBMCs and granulocytes in individuals with newly diagnosed T1D (less than 6 months), compared to healthy controls ( 133 ).…”