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.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease that occurs when immunological tolerance to self-tissues fails, resulting in the destruction of insulin-producing β cells in genetically predisposed individuals [1]
We found that AIM2 transcripts were increased in the pancreatic tissue of type 1 diabetes (T1D) patients, when compared to healthy controls (HC), but no significant alterations were observed in the peripheral blood
We demonstrate the importance of the sensor,AIM2, AIM2,in in the the control
Summary
Type 1 diabetes (T1D) is an autoimmune disease that occurs when immunological tolerance to self-tissues fails, resulting in the destruction of insulin-producing β cells in genetically predisposed individuals [1]. T1D triggers include viral infections, gut microbiota alterations and diet [3]. These environmental factors may act in the beginning or progression of the autoimmune disease that results in β cells damage [4]. STZ-induced diabetes represents an immune-mediated mouse model of T1D. In this context, splenocytes from STZ-injected mice causes insulin resistance and diabetes upon adoptive transfer [6,7]. Anti-insulin antibodies were found in the sera of naive
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