title: NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets.
abstract: Studies in animal models and human subjects have shown that both innate and adaptive immunity contribute to the pathogenesis of type 1 diabetes (T1D). Whereas the role of TLR signaling pathways in T1D has been extensively studied, the contribution of the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein (NLRP) 3 inflammasome pathway remains to be explored. In this study, we report that NLRP3 plays an important role in the development of T1D in the nonobese diabetic (NOD) mouse model. NLRP3 deficiency not only affected T-cell activation and Th1 differentiation, but also modulated pathogenic T-cell migration to the pancreatic islet. The presence of NLRP3 is critical for the expression of the chemokine receptors CCR5 and CXCR3 on T cells. More importantly, NLRP3 ablation reduced the expression of chemokine genes CCL5 and CXCL10 on pancreatic islet cells in an IRF-1-dependent manner. Our results suggest that molecules involved in chemotaxis, accompanied by the activation of the NLRP3 inflammasome, may be effective targets for the treatment of T1D.
authors: Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT 06520;
authors: Changyun
authors: C
authors: Hu
authors: Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT 06520; Endocrinology Section, The 5th People's Hospital, Fudan University, 200240 Shanghai, China;
authors: Heyuan
authors: H
authors: Ding
authors: Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT 06520;
authors: Yangyang
authors: Y
authors: Li
authors: Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT 06520;
authors: James A
authors: JA
authors: Pearson
authors: Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT 06520;
authors: Xiaojun
authors: X
authors: Zhang
authors: Howard Hughes Medical Institute, Yale University, New Haven, CT, 06519; and Department of Immunology, Yale University, New Haven, CT 06519; li.wen@yale.edu richard.flavell@yale.edu.
authors: Richard A
authors: RA
authors: Flavell
authors: Institute of Molecular and Experimental Medicine, Cardiff School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
authors: F Susan
authors: FS
authors: Wong
authors: Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT 06520; li.wen@yale.edu richard.flavell@yale.edu.
authors: Li
authors: L
authors: Wen
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D018946:Chemokine CCL5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002633:Chemotaxis / Q000235:genetics / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: C000592874:CCR5 protein, mouse; D002352:Carrier Proteins; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; C515188:Cxcr3 protein, mouse; D058847:Inflammasomes; D050856:Interferon Regulatory Factor-1; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D019713:Receptors, CCR5; D054367:Receptors, CXCR3
keywords: NLRP3; NOD mouse; chemokine; islet; type 1 diabetes