Thioredoxin-Interacting Protein Mediates ER Stress-Induced β Cell Death through Initiation of the Inflammasome

Oslowski, Christine M.; Hara, Takashi; O’Sullivan-Murphy, Bryan; Kanekura, Kohsuke; Lu, Simin; Hara, Mariko; Ishigaki, Shinsuke; Zhu, Lihua Julie; Hayashi, Emiko; Hui, Simon T.; Greiner, Dale L.; Kaufman, Randal J.; Bortell, Rita; Urano, Fumihiko

doi:10.1016/j.cmet.2012.07.005

Cited by 609 publications

(550 citation statements)

References 40 publications

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“…The mice fed a HFD were administered a chronic low dose of LPS before cold acclimation, which resulted in a reduced core body temperature and heat release, and elevated levels of endoplasmic reticulum stress and autophagy 90 . In addition to TLRs, endoplasmic reticulum stress is known to activate the NLRP3 inflammasome and induce apoptosis in pancreatic β cells 91,92 . This scenario has also been demonstrated in macrophages 93 and adipocytes 94 , and endoplasmic reticulum stress is sufficient for the production of IL1β via the activation of NFκB and the NLRP3 inflammasome.…”

Section: [H3] Er Stressmentioning

confidence: 99%

Innate immunity in diabetes and diabetic nephropathy

2015

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Abstract:The innate immune system consists of several classes of pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) and nucleotide-binding domain leucine-rich 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, IL1β, and IL18 and thus initiate 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 are critically involved in the inflammatory responses in pancreatic islets, adipose, liver and kidney tissues. This Review discusses how innate immune system-driven inflammatory processes can lead to apoptosis, tissue fibrosis, and organ dysfunction to cause insulin resistance, impaired insulin secretion, and renal failure. We propose that careful targeting of TLR2, TLR4, and NLRP3 signalling pathways may be beneficial for the treatment of diabetes mellitus and diabetic nephropathy. 2 Key points The innate immune system consists of several classes of pattern recognition receptors, including TLRs and NLRs, which detect pathogen-associated and danger-associated molecular patterns and initiate an inflammatory response  TLR2 and TLR4 are the predominant toll-like receptors expressed on pancreatic β cells that trigger an inflammatory response in insulitis during type 1 diabetes mellitus  TLR2 and TLR4 signaling, and activation of NLRP3 inflammasomes results in production of various proinflammatory cytokines that can induce insulin resistance in type 2 diabetes mellitus (T2DM) and obesity  Innate immune responses in T2DM and obesity are modulated by the status of the gut microbiota, autophagy, and adipokines  TLR2, TLR4, NOD2, and NLRP3 inflammasome-mediated inflammation are involved in the perpetuation of inflammation in diabetic nephropathy  The activation of TLRs and NLRs stimulates the expression of MCP-1, which is associated with the progression of diabetic nephropathy [H1] IntroductionThe prevalence of diabetes mellitus is estimated to be 8.3%, affecting ~387 million people as of 2014. The number of patients living with diabetes mellitus is expected to increase to ~592 million by 2035, as reported by the International Diabetes Federation 1 . The incidence of end-stage renal disease (ESRD) is also rapidly increasing worldwide but varies up to 15-fold by country. In 2012, the number of new diagnoses of ESRD worldwide ranged from 25 to 467 patients per million. The proportion of new cases of ESRD with diabetes mellitus as the primary cause also differs by country, with 66% cases reported in Singapore and 12-16% cases reported in Ukraine, Romania, and the Netherlands 2 . Although intensified multifactorial intervention in patients with type 2 diabete...

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Section: [H3] Er Stressmentioning

confidence: 99%

Innate immunity in diabetes and diabetic nephropathy

2015

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“…Moreover, ROS and lysosomal damage also activates NALP3 inflammasome pathway and induce proinflammatory reactions. Reports clearly indicate that ER stress induces pro IL1b and NLRP3 inflammasome activation [59,60] through NF-jB pathway. The findings thus surmise the role of ER stress in inflammatory pathways and its related diseases.…”

Section: Er Stress and Inflammatory Responsesmentioning

confidence: 99%

Role of Endoplasmic Reticulum Stress and Unfolded Protein Responses in Health and Diseases

2015

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Endoplasmic reticulum (ER) is the site of protein synthesis, protein folding, maintainance of calcium homeostasis, synthesis of lipids and sterols. Genetic or environmental insults can alter its function generating ER stress. ER senses stress mainly by three stress sensor pathways, namely protein kinase R-like endoplasmic reticulum kinase-eukaryotic translation-initiation factor 2a, inositol-requiring enzyme 1a-X-box-binding protein 1 and activating transcription factor 6-CREBH, which induce unfolded protein responses (UPR) after the recognition of stress. Recent studies have demonstrated that ER stress and UPR signaling are involved in cancer, metabolic disorders, inflammatory diseases, osteoporosis and neurodegenerative diseases. However, the precise knowledge regarding involvement of ER stress in different disease processes is still debatable. Here we discuss the possible role of ER stress in various disorders on the basis of existing literature. An attempt has also been made to highlight the present knowledge of this field which may help to elucidate and conjure basic mechanisms and novel insights into disease processes which could assist in devising better future diagnostic and therapeutic strategies.

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“…Increased ATF5 expression induces asparagine synthetase in acute lymphoblastic leukemia and reduces therapeutic treatment with L-asparaginase (Rousseau et al 2011). ATF5 can promote inflammatory responses upon ER stress in β cells by increasing transcription of thioredoxin-interacting protein (TXNIP) to activate the NLRP3 inflammasome to produce IL-1β (Oslowski et al 2012).…”

Section: Additional Tfsmentioning

confidence: 99%

Physiological/pathological ramifications of transcription factors in the unfolded protein response

2017

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Numerous environmental, physiological, and pathological insults disrupt protein-folding homeostasis in the endoplasmic reticulum (ER), referred to as ER stress. Eukaryotic cells evolved a set of intracellular signaling pathways, collectively termed the unfolded protein response (UPR), to maintain a productive ER protein-folding environment through reprogramming gene transcription and mRNA translation. The UPR is largely dependent on transcription factors (TFs) that modulate expression of genes involved in many physiological and pathological conditions, including development, metabolism, inflammation, neurodegenerative diseases, and cancer. Here we summarize the current knowledge about these mechanisms, their impact on physiological/pathological processes, and potential therapeutic applications.

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Thioredoxin-Interacting Protein Mediates ER Stress-Induced β Cell Death through Initiation of the Inflammasome

Cited by 609 publications

References 40 publications

Innate immunity in diabetes and diabetic nephropathy

Innate immunity in diabetes and diabetic nephropathy

Role of Endoplasmic Reticulum Stress and Unfolded Protein Responses in Health and Diseases

Physiological/pathological ramifications of transcription factors in the unfolded protein response

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