Toll-Like Receptors and Type 1 Diabetes

Zipris, Danny

doi:10.1007/978-90-481-3271-3_25

Cited by 38 publications

(25 citation statements)

References 161 publications

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“…It does not involve major differences in the composition of the gut bacteria, as we found that the gut microbiome in the LEW1.WR1 rat is similar to that of mice and humans, and is composed of two major bacterial phyla, Bacteroidetes and Firmicutes, and a few other less abundant types of bacteria. In any case, our findings are compatible with the overall notion that unlike the NOD mouse, microbial infection and TLRinduced innate activation promote anti-islet autoimmunity in the LEW1.WR1 model (22). Our data are also in agreement with previous reports demonstrating that antibiotic treatment (17) and the administration of Lactobacillus (20) prevent spontaneous disease in the diabetes-prone BB rat.…”

Section: Foxp3supporting

confidence: 93%

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Prevention of Virus-Induced Type 1 Diabetes with Antibiotic Therapy

Hara

Alkanani

et al. 2012

The Journal of Immunology

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111

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Microbes were hypothesized to play a key role in the progression of type 1 diabetes (T1D). We used the LEW1.WR1 rat model of Kilham rat virus (KRV)-induced T1D to test the hypothesis that the intestinal microbiota is involved in the mechanism leading to islet destruction. Treating LEW1.WR1 rats with KRV and a combination of trimethoprim and sulfamethoxazole (Sulfatrim) beginning on the day of infection protected the rats from insulitis and T1D. Pyrosequencing of bacterial 16S rRNA and quantitative RT-PCR indicated that KRV infection resulted in a transient increase in the abundance of Bifidobacterium spp. and Clostridium spp. in fecal samples from day 5- but not day 12-infected versus uninfected animals. Similar alterations in the gut microbiome were observed in the jejunum of infected animals on day 5. Treatment with Sulfatrim restored the level of intestinal Bifidobacterium spp. and Clostridium spp. We also observed that virus infection induced the expression of KRV transcripts and the rapid upregulation of innate immune responses in Peyer’s patches and pancreatic lymph nodes. However, antibiotic therapy reduced the virus-induced inflammation as reflected by the presence of lower amounts of proinflammatory molecules in both the Peyer’s patches and pancreatic lymph nodes. Finally, Sulfatrim treatment reduced the number of B cells in Peyer’s patches and downmodulated adaptive immune responses to KRV, but did not interfere with antiviral Ab responses or viral clearance from the spleen, pancreatic lymph nodes, and serum. The data suggest that gut microbiota may be involved in promoting virus-induced T1D in the LEW1.WR1 rat model.

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Section: Foxp3supporting

confidence: 93%

“…Infection of rats with Kilham rat virus (KRV) leads to T1D within 2-4 wk after viral inoculation in 50% of the infected rats (22). LEW1.WR1 rats have normal T lymphocyte levels and function (23), and the disease is characterized by a selective loss of islet b cells, glycosuria, ketonuria, and polyuria (23,24).…”

mentioning

confidence: 99%

Prevention of Virus-Induced Type 1 Diabetes with Antibiotic Therapy

Hara

Alkanani

et al. 2012

The Journal of Immunology

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111

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“…In agreement with this notion, our present study showed that diabetic Apoe K/K mice have increased expression of IL6 and MMP9 and content of infiltrated monocytes/macrophages in atherosclerotic lesions when compared with nondiabetic Apoe K/K mice. As TLR4 plays an important role in inflammation that is responsible for not only atherosclerosis but also diabetes (Bjorkbacka et al 2004, Michelsen et al 2004, Zipris 2010, Devaraj et al 2011, Grieco et al 2011, it is rational to postulate that TLR4 blockade with Rs-LPS in diabetic Apoe K/K mice would have higher impact than that in nondiabetic Apoe K/K mice on inflammation-related atherosclerosis. Indeed, the current study showed that Rs-LPS significantly reduced atherosclerotic lesions in diabetic Apoe K/K mice.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, in vitro studies have shown that minimally modified LDL (mmLDL) is capable of inducing inflammatory cytokine production in macrophages by engaging TLR4 (Miller et al 2003(Miller et al , 2005. Besides atherosclerosis, studies of diabetes in animal models have shown that deficiency of TLR4 is also associated with attenuation of the pro-inflammatory state of diabetes (Zipris 2010, Devaraj et al 2011, Grieco et al 2011. Thus, TLR4 appears to be a key player in the inflammatory processes contributing to both atherosclerosis and diabetes.…”

Section: Introductionmentioning

confidence: 99%

TLR4 antagonist reduces early-stage atherosclerosis in diabetic apolipoprotein E-deficient mice

Lu¹,

Zhang²,

Li³

et al. 2012

Journal of Endocrinology

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Although it has been reported that deficiency of toll-like receptor 4 (TLR4) is associated with reduced atherosclerosis in atherosclerosis-prone mice and attenuated pro-inflammatory state in diabetic mice, it remains undetermined whether treatment with a TLR4 antagonist reduces atherosclerosis in nondiabetic or diabetic mice that have TLR4 expression. In this study, we determined the effect of Rhodobacter sphaeroides lipopolysaccharide (Rs-LPS), an established TLR4 antagonist, on early-stage atherosclerosis in nondiabetic and streptozotocin-induced diabetic apolipoprotein E-deficient (Apoe K/K ) mice. Analysis of atherosclerotic lesions of both en face aortas and cross sections of aortic roots showed that administration of Rs-LPS in 14-week-old diabetic Apoe K/K mice for 10 weeks significantly reduced atherosclerotic lesions. Although atherosclerotic lesions in nondiabetic Apoe K/K mice appeared to be decreased by Rs-LPS treatment, the difference was not statistically significant. Metabolic study showed that Rs-LPS significantly lowered serum levels of cholesterol and triglycerides in nondiabetic mice but not in diabetic mice. Furthermore, immunohistochemistry studies showed that Rs-LPS inhibited the expression of interleukin 6 and matrix metalloproteinase-9 and reduced the content of monocytes and macrophages in atherosclerotic plaques. Taken together, this study demonstrated for the first time that TLR4 antagonist inhibited vascular inflammation and atherogenesis in diabetic Apoe K/K mice and lowered serum cholesterol and triglyceride levels in nondiabetic Apoe K/K mice.

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“…TLRs also play a crucial role in inflammation-associated diseases (48), including diabetes mellitus (56) or atherosclerosis (33). Most studies have shown a proatherogenic role for TLRs (34).…”

Section: Expression Of Genes Related To Nf-b Pathway In Crpstimulatedmentioning

confidence: 99%

NF-κB pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension

Wynants

Vengethasamy

Ronisz

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Wynants M, Vengethasamy L, Ronisz A, Meyns B, Delcroix M, Quarck R. NF-B pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 305: L934-L942, 2013. First published October 4, 2013 doi:10.1152/ajplung.00034.2013.-Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombofibrotic obstruction of proximal pulmonary arteries. The cellular and molecular mechanisms underlying the pathogenesis remain incompletely understood, although we recently evidenced the potential involvement of the inflammatory marker C-reactive protein (CRP). We aimed to investigate the intracellular mechanisms induced by CRP in proximal pulmonary arterial endothelial cells (PAEC). PAEC were isolated from vascular material obtained during pulmonary endarterectomy. RNA was extracted from CRP-stimulated PAEC, and first-stand cDNA was generated. A RT 2 profiler PCR Array was used to evaluate the expression of 84 key genes related to NF-B-mediated signal transduction. CRP-induced NF-B activation was studied. The effects of pyrrolidine-dithio-carbamate ammonium (PDTC), an inhibitor of the NF-B pathway, were investigated on CRP-induced adhesion of monocytes to PAEC, adhesion molecule expression, endothelin-1 (ET-1), interleukin-6 (IL-6), and von Willebrand factor (vWF) secretion. Compared with nonstimulated PAEC, serotonin receptor 2B was downregulated by 25%, inhibitor of NF-B kinase subunit epsilon (IKBKE) by 30%, and toll-like receptor-4 and -6 by 18 and 39%, respectively, in CRP-stimulated PAEC. The transcription factor FOS was threefold upregulated. CRP induced RelA/NF-Bp65 phosphorylation. PDTC dose dependently inhibited the adhesion of monocytes to CRP-stimulated PAEC. PDTC also inhibited the CRP-induced expression of ICAM-1 at the surface of PAEC. PDTC impaired the secretion of ET-1 by 18% and tended to inhibit the secretion of IL-6 by CRP-stimulated PAEC by 46%. PDTC did not inhibit the CRP-induced secretion of vWF. These results suggest an involvement of the NF-B pathway in mediating different effects of CRP on proximal CTEPH-PAEC. C-reactive protein; endothelial cells; NF-B; chronic thromboembolic pulmonary hypertension CHRONIC THROMBOEMBOLIC PULMONARY hypertension (CTEPH) is a severe cause of pulmonary hypertension characterized by an obliteration of proximal pulmonary arteries by intraluminal thrombi and fibrous stenosis. Pulmonary embolism, either as single or recurrent episodes, is thought to be the initiating event followed by progressive pulmonary vascular remodeling. Vascular disobliteration by pulmonary endarterectomy (PEA) is the preferred treatment for CTEPH patients (38).Knowledge of the physiopathology of CTEPH remains incomplete. Proximal lesions share similarities with atherosclerotic plaques, including media thickening and neointima formation (1). Risk factors for CTEPH include size of the initial thrombus, elevated factor VIII, circulating phospholipid antibodies, and fibrinogen intrinsic ...

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Toll-Like Receptors and Type 1 Diabetes

Cited by 38 publications

References 161 publications

Prevention of Virus-Induced Type 1 Diabetes with Antibiotic Therapy

Prevention of Virus-Induced Type 1 Diabetes with Antibiotic Therapy

TLR4 antagonist reduces early-stage atherosclerosis in diabetic apolipoprotein E-deficient mice

NF-κB pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension

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