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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Leite, Jefferson Antonio [1, 2] ; Pessenda, Gabriela [1] ; Guerra-Gomes, Isabel C. [1] ; Mendonca de Santana, Alynne Karen [1] ; Pereira, Camila Andre [3] ; Campos Costa, Frederico Ribeiro [1] ; Ramos, Simone G. [4] ; Zamboni, Dario Simoes [5] ; Caetano Faria, Ana Maria [6] ; de Almeida, Danilo Candido [7] ; Saraiva Camara, Niels Olsen [1, 2, 7] ; Tostes, Rita C. [3] ; Silva, Joao Santana [8] ; Carlos, Daniela [1]
Total Authors: 14
[1] Ribeirao Preto Med Sch, Dept Biochem & Immunol, USP Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil
[2] Univ Sao Paulo, Inst Biomed Sci 4, BR-14049900 Sao Paulo, SP - Brazil
[3] Univ Sao Paulo, Dept Pharmacol, Ribeirao Preto Med Sch, BR-14049900 Ribeirao Preto, SP - Brazil
[4] Univ Sao Paulo, Dept Pathol & Legal Med, Ribeirao Preto Med Sch, BR-14049900 Ribeirao Preto, SP - Brazil
[5] Univ Sao Paulo, Dept Mol & Cell Biol, Ribeirao Preto Med Sch, BR-14049900 Ribeirao Preto, SP - Brazil
[6] Fed Univ Minas Gerais UFMG, Dept Biochem & Immunol, Inst Biol Sci, BR-31270901 Belo Horizonte, MG - Brazil
[7] Fed Univ Sao Paulo UNIFESP, Dept Immunol, BR-04021001 Sao Paulo, SP - Brazil
[8] Fiocruz Bi Inst Translat Med Platform, BR-14049900 Ribeirao Preto, SP - Brazil
Total Affiliations: 8
Document type: Journal article
Source: CELLS; v. 9, n. 4 APR 2020.
Web of Science Citations: 0

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 RegIII gamma 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 beta cells, which ultimately results in protection against T1D onset in an STZ-induced diabetes model. (AU)

FAPESP's process: 12/10395-0 - Role of NLRs receptors in immunoregulation mechanisms of the type 1 and 2 diabetes: identification of potential therapeutic targets
Grantee:Daniela Carlos Sartori
Support Opportunities: Research Grants - Young Investigators Grants
FAPESP's process: 16/25116-0 - Evaluation of the expression profile and function of AIM2 inflammasome in intestinal mucosa during diabetes type 1 experimental
Grantee:Jefferson Antonio Leite
Support Opportunities: Scholarships in Brazil - Master
FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
Grantee:Fernando de Queiroz Cunha
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC