文章基本信息

标题：NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets
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作者：Changyun Hu ; Heyuan Ding ; Yangyang Li 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：36
页码：11318-11323
DOI：10.1073/pnas.1513509112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceOur study demonstrated that the nucleotidebinding oligomerization domain, leucine-rich repeat and pyrin domaincontaining protein 3 (NLRP3) pathway plays an important role in type 1 diabetes (T1D) using a mouse model. NLRP3 is critical for chemokine receptors CCR5 and CXCR3 expression on T cells, influencing pathogenic T-cell migration to the islets. It also affects the chemokines CCL5 and CXCL10 expression in the islets, preventing pathogenic T cells from infiltration. Targeting this pathway may be useful in prevention and treatment of T1D as it affects both immune cells and pancreatic beta cells. 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.
关键词：NLRP3 ; islet ; type 1 diabetes ; chemokine ; NOD mouse