Toll-Like Receptor Signaling Pathways

Kawasaki, Takumi; Kawai, Taro

doi:10.3389/fimmu.2014.00461

Cited by 2,645 publications

(2,476 citation statements)

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“…6a). For example, TLR7, whose role in nucleic acid sensing, B cell activation and differentiation is well established 34,35 is expressed in our data in pDCs, myeloid . CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”

Section: Cluster-specific Expression Of Genes Associated With Diseasementioning

confidence: 82%

The immune cell landscape in kidneys of lupus nephritis patients

Arazi

Rao

Berthier

et al. 2018

Preprint

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Lupus nephritis is a potentially fatal autoimmune disease, whose current treatment is ineffective and often toxic. To gain insights into disease mechanisms, we analyzed kidney samples from lupus nephritis patients and healthy controls using single-cell RNA-seq. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid, T, NK and B cells, demonstrating both pro-inflammatory and resolving responses. We found evidence of local activation of B cells correlated with an age-associated B cell signature, and of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, pointing to potential therapeutic targets. Gene expression of immune cells in urine and kidney was highly correlated, suggesting urine may be a surrogate for kidney biopsies. Our results provide a first comprehensive view of the complex network of leukocytes active in lupus nephritis kidneys.

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Section: Cluster-specific Expression Of Genes Associated With Diseasementioning

confidence: 82%

The immune cell landscape in kidneys of lupus nephritis patients

Arazi

Rao

Berthier

et al. 2018

Preprint

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Section: [H2] Inflammasomesmentioning

confidence: 99%

“…The TIR domain consists of three boxes of conserved residues set in a core sequence of 135-160 amino acids, which facilitate receptor-adaptor oligomerization 14 . The differential recruitment of these adaptor proteins results in the formation of a myddosome complex-an oligomeric signaling complex that consists of the adaptor proteins MyD88, IRAK1 and IRAK4-and activation of various signaling molecules, such as NFκB, MAPK, and interferon regulatory factor (IRF) and the subsequent production and release of various cytokines and chemokines ( Figure 1; Table 1) [15][16][17][18][19] .…”

Section: [H1] Prrs Of the Innate Immune System [H2] Toll-like Receptorsmentioning

confidence: 99%

“…NLRP1 or NLRP3 oligomerize via the NACHT domain (a 300-400 amino acid NTPase domain), which results in subsequent PYD clustering and the recruitment of PYCARD, which contains a caspase recruitment domain (ASC) to activate caspase-1. Activation of caspase-1 promotes the processing and secretion of IL1β, IL18, and IL33 (Figure 2) 7,19,28 .[H1] Type 1 diabetes mellitus (T1DM)[H2] Involvement of TLRs T1DM is a well-established type 1 T helper (TH1) cell-mediated disease whereby pancreatic β cells are selectively injured and destroyed 29 . Many of the studies that have addressed the mechanisms of T1DM have mainly focused on the role of the adaptive immune system that is mediated by T lymphocytes.…”

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confidence: 99%

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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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“…Th ey are pattern recognition receptors (PRRs), which recognize antigens with repeated pathogen-associated molecular patterns (PAMPs). Th eir activation induces a cascade signaling with a fi nal eff ect -transcription of genes of infl ammatory cytokines through the NFκB pathway (Kawasaki and Kawai 2014). Cytokines are involved in phosphorylation of insulin receptor substrates and further changes in post-receptor signaling.…”

mentioning

confidence: 99%

TLR4 polymorphisms seem not to be associated with prediabetes and type 2 diabetes but predispose to diabetic retinopathy; TLR4 polymorphisms in glucose continuum

Zaharieva

Kamenov

Savov

2017

Endocrine Regulations

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Objectives. Compared to type 1 diabetes, the role of the immune and autoimmune pathogenetic mechanisms is much less studied in the type 2 diabetes. Toll-like receptors 4 (TLR4) have a leading role in infl ammation, insulin resistance, and vascular damage. Th is study aimed to analyze the relationship between the polymorphisms in TLR4 gene and diff erent stages in the glucose continuum from prediabetes to the type 2 diabetes and chronic microvascular complications.Materials and Methods. Th e study included 113 patients with the type 2 diabetes, 29 participants with prediabetes, and 28 controls. Polymerase chain reaction (PCR) was used for genotyping Asp299Gly and Th r399Ile polymorphism, followed by restriction analysis.Results. Th e diff erence in the genotype frequency for both polymorphisms in patients with the type 2 diabetes or prediabetes compared to that in controls was not signifi cant. Patients with heterozygous genotype of Asp299Gly polymorphism had a higher prevalence of diabetic retinopathy (42.9%) than participants with homozygous genotype (9.0%) (OR [95%CI]=7.61 [1.41-41.08]; p=0.018). No association was established for diabetic polyneuropathy and nephropathy. Prevalence of chronic diabetes complications was not related to Th r399Ile polymorphism.Conclusion. Our study demonstrates that Asp299Gly and Th r399Ile polymorphisms seem not to be associated with the type 2 diabetes and prediabetes but Asp299Gly may contribute to diabetic retinopathy predisposition.

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Toll-Like Receptor Signaling Pathways

Cited by 2,645 publications

References 84 publications

The immune cell landscape in kidneys of lupus nephritis patients

The immune cell landscape in kidneys of lupus nephritis patients

Innate immunity in diabetes and diabetic nephropathy

TLR4 polymorphisms seem not to be associated with prediabetes and type 2 diabetes but predispose to diabetic retinopathy; TLR4 polymorphisms in glucose continuum

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