Expression of Toll-Like Receptor 2 in Glomerular Endothelial Cells and Promotion of Diabetic Nephropathy by Porphyromonas gingivalis Lipopolysaccharide

Sawa, Yoshihiko; Takata, Shunsuke; Hatakeyama, Yuji; Ishikawa, Hiroyuki; Tsuruga, Eichi

doi:10.1371/journal.pone.0097165

Cited by 34 publications

(35 citation statements)

References 36 publications

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“…P.g. has many pathogenic factors including fimbria, bacterial DNA, gingipain and LPS [6][7][8][9][10]13,23,24 . It was reported that gingipain, a trypsin-like cysteine protease, activated PAR2 in oral epithelial cells, gingival fibroblasts and immune cells in the periodontal tissue to produce cytokines including IL-6, 8 and MMP-2 resulting in periodontal breakdown 23,24 .…”

Section: Discussionmentioning

confidence: 99%

Odontogenic infection by Porphyromonas gingivalis exacerbates fibrosis in NASH via hepatic stellate cell activation

Nagasaki

Sakamoto

Chea

et al. 2020

Sci Rep

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odontogenic infection of Porphyromonas gingivalis (P.g.), a major periodontal pathogen, exacerbates pathological progression of non-alcoholic steatohepatitis (NASH). In this study, we aimed to clarify the detailed mechanism in which P.g. induced hepatic stellate cells (HSCs; key effector cells in liver fibrosis) activation. In the liver of high fat diet-induced NASH mouse model with P.g. odontogenic infection, immunolocalization of P.g. was detected. The number of hepatic crown-like structure, which was macrophage aggregation and related to liver fibrosis, was drastically increased and fibrosis area was also increased through upregulating immunoexpression of Phosphorylated Smad2 (key signaling molecule of TGF-β1) and Galectin-3. P.g.-secreted trypsin-like enzyme [gingipain; an activator of protease-activated receptor 2 (PAR2)] stimulated HSC proliferation and differentiation through Smad and ERK signaling induced by TGF-β1 produced from HSCs with P.g.-infection. Further, Galectin-3 produced from HSCs with P.g. infection and P.g.-derived LPS/lipoprotein stimulation stabilized TGFβ-receptor II resulting in increasing sensitivity for TGF-β1, finally leading to HSC differentiation via activating Smad and ERK signaling. In addition to them, hepatocytes (main component cells of liver) contributed to HSC activation through TGF-β1 and Galectin-3 production in paracrine manner. Collectively, P.g.-odontogenic infection exacerbates fibrosis of NASH by HSC activation through TGF-β1 and Gal-3 production from HSCs and hepatocytes.Non-alcoholic fatty liver disease (NAFLD) is a chronic hepatic disease caused by obesity including simple steatosis and non-alcoholic steatohepatitis (NASH). The morbidity rate of NAFLD is high, up to 30% in Western countries, with increasing the number of NAFLD patients because of the increase of obesity 1-3 . Most NAFLD patients indicate simple steatosis, which is a reversible condition, but 10-20% of simple steatosis progresses to NASH, which is presented as inflammation with hepatocyte degeneration followed by hepatic fibrosis 3 . As some of the NASH cases eventually result in liver cirrhosis and cancer, it is a critical health problem requiring adequate prevention and early therapeutic intervention 2,4 . The mechanisms for the development and progression of NASH are extremely complicated. Recently, it was reported that fat deposition, inflammation and fibrosis in NASH are simultaneously caused by many factors such as up-regulation of free fatty acids (FFA), oxidation stress, cytokines and bacterial lipopolysaccharide (LPS) 5 .Porphyromonas gingivalis (P.g.) is a main periodontal pathogen. Periodontitis caused by P.g. is a well-recognized risk factor for many systemic diseases such as cardiovascular disease, preterm birth, diabetes mellitus, and rheumatoid arthritis 6-9 . P.g. can enter the blood circulation from periodontal disease sites and disseminate into the whole body and it can be detected in the distant organs including liver 6,7,10,11 . Furusho et al. reported that P.g.-odontogenic infect...

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Section: Discussionmentioning

confidence: 99%

Odontogenic infection by Porphyromonas gingivalis exacerbates fibrosis in NASH via hepatic stellate cell activation

Nagasaki

Sakamoto

Chea

et al. 2020

Sci Rep

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“…Peritoneal and kidney macrophages were predominantly M1 phenotype in wild-type mice, and phenotypic changes of macrophages, podocyte loss and urinary albumin excretion were attenuated in Tlr2 -/--deficient mice 140 . In STZ-induced and HFD-induced diabetic mice, TLR2 localized on glomerular endothelial cells and repeated Porphyromonas gingivalis LPS administration enhanced urinary albumin excretion and production of IL6, TNF and LTA (TNFβ) in glomeruli 141 . In human proximal tubular cells, HMGB1-induced NFκB activation was prevented by TLR2 silencing, and the researchers of this study emphasized the importance of TLR2 as a mediator of NFκB activation in diabetic nephropathy 142 .…”

Section: [H3] Tlr2mentioning

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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“…The mechanisms that induce the inflammatory response in the kidney may share a common pathway: pro-inflammatory response upon toll-like receptors (TLRs) activation 5,6 . They suggest that different TLRs play a varying role in renal I/R of diabetes mellitus 5,7,8 . However, the role of TLR7 in renal I/R of diabetic has not been examined.…”

Section: Introducionmentioning

confidence: 99%

Toll-like receptor 7 involves the injury in acute kidney ischemia/reperfusion of STZ-induced diabetic rats

et al. 2016

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PURPOSE:To determine whether Toll-like receptor 7 (TLR7) is the potential targets of prevention or progression in the renal ischemia/ reperfusion (I/R) injury of STZ-induced diabetic rats. METHODS:Thirty six Sprague-Dawley rats were randomly arranged to the nondiabetic (ND) or diabetic group (DM), with each group further divided into sham (no I/R injury), I/R (ischemia-reperfusion) and CD (given by Chloroquine) group. Preoperatively, Chloroquine (40 mg/kg, intraperitoneal injection.) was administrated 6 days for treatment group. I/R animals were subjected to 25 min of bilateral renal ischemia. Renal function, histology, apoptosis, cytokines, expression of TLR7, MyD88 and NF-κB were detected. RESULTS:The serum levels of blood urea nitrogen, creatinine, IL-6 and TNF-α, apoptotic tubular epithelial cells, expression of TLR7, MyD88 and NF-κB were significantly increased in DM+I/R group, compared with ND+I/R group (p<0.05). All these changes were further improved by TLR7 inhibition Chloroquine except Paller scores (p<0.05). CONCLUSION:Toll-like receptor 7 inhibition attenuates the acute renal ischemia/reperfusion injury of STZ-induced diabetic in SD rats.

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Expression of Toll-Like Receptor 2 in Glomerular Endothelial Cells and Promotion of Diabetic Nephropathy by Porphyromonas gingivalis Lipopolysaccharide

Cited by 34 publications

References 36 publications

Odontogenic infection by Porphyromonas gingivalis exacerbates fibrosis in NASH via hepatic stellate cell activation

Odontogenic infection by Porphyromonas gingivalis exacerbates fibrosis in NASH via hepatic stellate cell activation

Innate immunity in diabetes and diabetic nephropathy

Toll-like receptor 7 involves the injury in acute kidney ischemia/reperfusion of STZ-induced diabetic rats

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