Toll-like receptors and NLRP3 as central regulators of pancreatic islet inflammation in type 2 diabetes.
The global health and economic burden of type 2 diabetes (T2D) has reached staggering proportions. Current projections estimate that 592 million people will have diabetes by 2035. T2D-which comprises 90% of cases-is a complex disease, in most cases resulting from a combination of predisposing genes and an unhealthy environment. Clinical onset of the disease occurs when pancreatic β cells fail in the face of insulin resistance. It has long been appreciated that chronic activation of the innate immune system is associated with T2D, and many organs critical to the regulation of glucose homeostasis show signs of a chronic inflammatory process, including the pancreatic islets of Langerhans. Recent clinical trials using IL-1-targeting agents have confirmed that inflammation contributes to β-cell failure in humans with T2D. However, little is known about the nature of the pro-inflammatory response within the islet, and there is considerable debate about the triggers for islet inflammation, which may be systemically derived and/or tissue-specific. In this review, we present evidence that Toll-like receptors 2 and 4 and the NLRP3 (Nucleotide-binding oligomerization domain, Leucine-rich Repeat and Pyrin domain containing 3) inflammasome are triggers for islet inflammation in T2D and propose that the activation of macrophages by these triggers mediates islet endocrine cell dysfunction. Therapeutically targeting these receptors may improve hyperglycemia and protect the β cell in T2D.
Department of Pathology and Laboratory Medicine, Faculty of Medicine, The University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada.
Clara
C
Westwell-Roper
Department of Surgery, Faculty of Medicine, The University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada.
Dominika
D
Nackiewicz
Department of Surgery, Faculty of Medicine, The University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada.
Meixia
M
Dan
Department of Surgery, Faculty of Medicine, The University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada.
Jan A
JA
Ehses
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000473:pathology*; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D051193:Toll-Like Receptors / Q000378:metabolism*
D002352:Carrier Proteins; D051193:Toll-Like Receptors