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

Autor(es):Mostrar menos -

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: CELLS; v. 9, n. 4 APR 2020.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 12/10395-0 - Papel dos receptores NLRs nos mecanismos de imunoregulação do diabetes do tipo 1 e 2: identificação de novos alvos terapêuticos
• Beneficiário: Daniela Carlos Sartori
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 16/25116-0 - Avaliação do perfil de expressão e função do inflamassoma AIM2 na mucosa intestinal no diabetes tipo 1 experimental
• Beneficiário: Jefferson Antonio Leite
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs