1. The DNA Sensor AIM2 Protects against Streptozotocin-Induced Type 1 Diabetes by Regulating Intestinal Homeostasis via the IL-18 Pathway.
- Author
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Leite JA, Pessenda G, Guerra-Gomes IC, de Santana AKM, André Pereira C, Ribeiro Campos Costa F, Ramos SG, Simões Zamboni D, Caetano Faria AM, Candido de Almeida D, Olsen Saraiva Câmara N, Tostes RC, Santana Silva J, and Carlos D
- Subjects
- Animals, Homeostasis, Humans, Interleukin-18 metabolism, Male, Mice, Mice, Inbred C57BL, DNA-Binding Proteins therapeutic use, Diabetes Mellitus, Experimental genetics, Immunity, Innate genetics
- 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.- Published
- 2020
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