Key Points
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The innate immune system consists of several classes of pattern recognition receptors, including Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), which detect pathogen-associated and danger-associated molecular patterns and initiate an inflammatory response
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TLR2 and TLR4 are the predominant TLRs expressed on pancreatic β cells which trigger an inflammatory response that results in insulitis during type 1 diabetes mellitus
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TLR2 and TLR4 signalling, and activation of NLRP3 inflammasomes result in the production of various proinflammatory cytokines that can induce insulin resistance in type 2 diabetes mellitus (T2DM) and obesity
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Innate immune responses in T2DM and obesity are modulated by the status of the gut microbiota, autophagy, and adipokines
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TLR2, TLR4, NOD2, and NLRP3 inflammasome-mediated inflammation are involved in the perpetuation of inflammation in diabetic nephropathy
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The activation of TLRs and NLRs stimulates the expression of MCP-1, which is associated with the progression of diabetic nephropathy
Abstract
The innate immune system includes several classes of pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). These receptors detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the extracellular and intracellular space. Intracellular NLRs constitute inflammasomes, which activate and release caspase-1, IL-1β, and IL-18 thereby initiating an inflammatory response. Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the development and progression of diabetes mellitus and diabetic nephropathy. TLR2, TLR4, and the NLRP3 inflammasome can induce the production of various proinflammatory cytokines and are critically involved in inflammatory responses in pancreatic islets, and in adipose, liver and kidney tissues. This Review describes how innate immune system-driven inflammatory processes can lead to apoptosis, tissue fibrosis, and organ dysfunction resulting in insulin resistance, impaired insulin secretion, and renal failure. We propose that careful targeting of TLR2, TLR4, and NLRP3 signalling pathways could be beneficial for the treatment of diabetes mellitus and diabetic nephropathy.
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Acknowledgements
J.W. and H.M. are supported in part by grants from the Japanese Society for the Promotion of Science Grant-in-Aid for Scientific Research (grant numbers 25126716 and 26293218). The authors would like to thank Dr Atsuko Nakatsuka (Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan) for valuable discussion and critical editing of the manuscript.
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J.W. researched the data and wrote the article. J.W. and H.M. provided a substantial contribution to discussions of the content and to review and/or editing of the manuscript before submission.
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J.W. receives speaker honoraria from Astellas, Boehringer Ingelheim, Novartis, Novo Nordisk, and Tanabe Mitsubishi, and receives grant support from Bayer, Daiichi Sankyo, Kyowa Hakko Kirin, MSD, Novo Nordisk, Otsuka, Torii, Pfizer, Takeda, Taisho Toyama, and Tanabe Mitsubishi. H.M. is a consultant for AbbVie, Astellas and Teijin, receives speaker honoraria from Astellas, Boehringer-Ingelheim, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, MSD, Novartis, Pfizer, Takeda, and Tanabe Mitsubishi, and receives grant support from Astellas, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, MSD, Novo Nordisk, Takeda, and Tanabe Mitsubishi.
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Wada, J., Makino, H. Innate immunity in diabetes and diabetic nephropathy. Nat Rev Nephrol 12, 13–26 (2016). https://doi.org/10.1038/nrneph.2015.175
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DOI: https://doi.org/10.1038/nrneph.2015.175
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