Gut microbiota translocation to the pancreatic lymph nodes triggers NOD2 activation and contributes to T1D onset

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Costa, Frederico R. C. ; Francozo, Marcela C. S. ; de Oliveira, Gabriela G. ; Ignacio, Aline ; Castoldi, Angela ; Zamboni, Dario S. ; Ramos, Simone G. ; Camara, Niels O. ; de Zoete, Marcel R. ; Palm, Noah W. ; Flavell, Richard A. ; Silva, Joao S. ; Carlos, Daniela

• Document type: Journal article
• Source: JOURNAL OF EXPERIMENTAL MEDICINE; v. 213, n. 7, p. 1223-1239, JUN 27 2016.
• Web of Science Citations: 34

Abstract

Type 1 diabetes (T1D) is an autoimmune disease that is triggered by both genetic and environmental factors, resulting in the destruction of pancreatic beta cells. The disruption of the intestinal epithelial barrier and consequent escape of microbial products may be one of these environmental triggers. However, the immune receptors that are activated in this context remain elusive. We show here that during streptozotocin (STZ)-induced T1D, the nucleotide-binding oligomerization domain containing 2 (NOD2), but not NOD1, participates in the pathogenesis of the disease by inducing T helper 1 (Th1) and Th17 cells in the pancreatic LNs (PLNs) and pancreas. Additionally, STZ-injected wild-type (WT) diabetic mice displayed an altered gut microbiota compared with vehicle-injected WT mice, together with the translocation of bacteria to the PLNs. Interestingly, WT mice treated with broad-spectrum antibiotics (Abx) were fully protected from STZ-induced T1D, which correlated with the abrogation of bacterial translocation to the PLNs. Notably, when Abx-treated STZ-injected WT mice received the NOD2 ligand muramyl dipeptide, both hyperglycemia and the proinflammatory immune response were restored. Our results demonstrate that the recognition of bacterial products by NOD2 inside the PLNs contributes to T1D development, establishing a new putative target for intervention during the early stages of the disease. (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: 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