Gut microbiota translocation to the pancreatic lymph nodes triggers NOD2 activation and contributes to T1D onset.
Type 1 diabetes (T1D) is an autoimmune disease that is triggered by both genetic and environmental factors, resulting in the destruction of pancreatic β 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.
Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, São Paulo, Brazil.
Frederico R C
FR
Costa
Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, São Paulo, Brazil.
Marcela C S
MC
Françozo
Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, São Paulo, Brazil.
Gabriela G
GG
de Oliveira
Department of Immunology, Institute of Biomedical Science (ICB), University of São Paulo, 05508-000 São Paulo, Brazil.
Aline
A
Ignacio
Department of Immunology, Institute of Biomedical Science (ICB), University of São Paulo, 05508-000 São Paulo, Brazil.
Angela
A
Castoldi
Department of Molecular and Cell Biology, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, São Paulo, Brazil.
Dario S
DS
Zamboni
Department of Pathology, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, São Paulo, Brazil.
Simone G
SG
Ramos
Department of Immunology, Institute of Biomedical Science (ICB), University of São Paulo, 05508-000 São Paulo, Brazil.
Niels O
NO
Câmara
Department of Immunobiology, Yale University School of Medicine, The Anlyan Center, New Haven, CT 06519 Howard Hughes Medical Institute, Yale University, New Haven, CT 06510 Department of Infectious Diseases and Immunology, Utrecht University, 3584 CL Utrecht, the Netherlands.
Marcel R
MR
de Zoete
Department of Immunobiology, Yale University School of Medicine, The Anlyan Center, New Haven, CT 06519.
Noah W
NW
Palm
Department of Immunobiology, Yale University School of Medicine, The Anlyan Center, New Haven, CT 06519 Howard Hughes Medical Institute, Yale University, New Haven, CT 06510.
Richard A
RA
Flavell
Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, São Paulo, Brazil.
João S
JS
Silva
Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, São Paulo, Brazil danicar@usp.br.
Daniela
D
Carlos
D000818:Animals; D018988:Bacterial Translocation / Q000235:genetics / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D000069196:Gastrointestinal Microbiome; D008198:Lymph Nodes / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology*; D010179:Pancreas / Q000276:immunology / Q000382:microbiology / Q000473:pathology
D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse