Mycobacterial heat shock protein 65 (mbHSP65)-induced atherosclerosis: Preventive oral tolerization and definition of atheroprotective and atherogenic mbHSP65 peptides

Grundtman, Cecilia; Jakic, Bojana; Buszko, Maja; Onestingel, Elisabeth; Almanzar, Giovanni; Demetz, Egon; Dietrich, Hermann; Cappellano, Giuseppe; Wick, Georg

doi:10.1016/j.atherosclerosis.2015.06.044

Cited by 32 publications

(12 citation statements)

References 34 publications

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“…In the early stage of atherosclerosis, production of oxidized LDL (ox-LDL) and formation of atherosclerotic plaque is mainly caused by activated vessel immune cells with excessive inflammatory responses provoked by pathogen recognition receptors, including TLRs; however, findings of TLR-mediated atheroprotective effects have also emerged [ 15 ]. For example, a heat shock protein, which acts as TLR4 agonist, was found to show preventive effects against hyperlipidemia and atherosclerosis when administered orally to apoE-deficient mice [ 16 ]. In our previous clinical study, oral administration of the LPSp-containing tea resulted in a significant reduction in levels of fasting plasma glucose and low-density lipoprotein (LDL) cholesterol in hyperlipidemic volunteers with no adverse effects [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Oral administration of Pantoea agglomerans-derived lipopolysaccharide prevents development of atherosclerosis in high-fat diet-fed apoE-deficient mice via ameliorating hyperlipidemia, pro-inflammatory mediators and oxidative responses

et al. 2018

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Pantoea agglomerans (P. agglomerans) is a Gram-negative bacterium that grows symbiotically with various edible plants, and the oral or sublingual administration of lipopolysaccharide derived from P. agglomerans (LPSp) have been suggested to contribute to prevention of immune-related diseases. Our previous study indicated that orally administered LPSp was shown to exhibit an LDL-lowering effect in hyperlipidemic volunteers; however, a preventive effect of LPSp on atherosclerosis is unclear. The present study attempted to evaluate the anti-atherosclerotic effect by LPSp in a mouse model of high-fat diet (HFD)-induced atherosclerosis. For 16 weeks, apoE-deficient mice were fed an HFD and received drinking water containing LPSp (0.3 or 1 mg/kg body weight/day). The results showed that the orally administered LPSp decreased body weight. A significant reduction in atherosclerotic plaque deposition was observed even with the lower dose of LPSp. The biochemical analyses showed that LPSp markedly improved glucose tolerance and reduced plasma LDL and oxidized LDL levels. In addition, LPSp significantly reduced the production of pro-inflammatory mediators including MCP-1 (in the plasma), TNF-α and IL-6 (in the colon), and decreased the oxidative burst activities in the peripheral blood sample. Taken together, these results suggest the possibility that oral administration of LPSp can effectively ameliorate HFD-induced hyperlipidemia and inflammatory/oxidative responses to prevent atherosclerosis and related metabolic disorders.

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Section: Introductionmentioning

confidence: 99%

Oral administration of Pantoea agglomerans-derived lipopolysaccharide prevents development of atherosclerosis in high-fat diet-fed apoE-deficient mice via ameliorating hyperlipidemia, pro-inflammatory mediators and oxidative responses

et al. 2018

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“…Our recent in vivo study demonstrated that oral administration of LPSp prevented the development of atherosclerosis via reducing hyperlipidemia, pro-inflammatory mediators and oxidative responses in high-fat diet (HFD)-fed mice [ 16 ]. Other studies also reported that oral treatment with a heat shock protein (HSP; known as a TLR4 agonist) prevents the development of diabetes mellitus and hyperlipidemia by improving glucose/lipid metabolism and reducing inflammatory responses in mice [ 17 , 18 ], however few studies have shown a preventive effect on AD progression by orally administered TLR4 agonists. Our in vitro studies have demonstrated that LPSp significantly increases phagocytic activity directed at Aβ 1–42 peptides in a mouse microglial cell line and primary microglia isolated from mouse brain [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Oral administration of Pantoea agglomerans-derived lipopolysaccharide prevents metabolic dysfunction and Alzheimer’s disease-related memory loss in senescence-accelerated prone 8 (SAMP8) mice fed a high-fat diet

et al. 2018

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The pathogenesis of Alzheimer’s disease (AD) remains unclear, but an imbalance between the production and clearance of amyloid-β (Aβ) peptides is known to play a critical role in AD progression. A promising preventative approach is to enhance the normal Aβ clearance activity of brain phagocytes such as microglia. In mice, the intraperitoneal injection of Toll-like receptor 4 agonist was shown to enhance Aβ clearance and exhibit a preventative effect on AD-related pathology. Our previous clinical study demonstrated that orally administered Pantoea agglomerans-derived lipopolysaccharide (LPSp) exhibited an LDL (low-density lipoprotein)-lowering effect in human volunteers with hyperlipidemia, a known risk factor for AD. In vitro studies have shown that LPSp treatment increases Aβ phagocytosis by microglial cells; however it is still unclear whether orally administered LPSp exhibits a preventive effect on AD progression. We show here that in senescence-accelerated prone 8 (SAMP8) mice fed a high-fat diet, oral administration of LPSp at 0.3 or 1 mg/kg body weight·day for 18 weeks significantly improved glucose metabolism and lipid profiles. The LPSp treatment also reduced pro-inflammatory cytokine expression and oxidative-burst activity in the peripheral blood. Moreover, LPSp significantly reduced brain Aβ burden and memory impairment as seen in the water maze test, although we could not confirm a significant enhancement of Aβ phagocytosis in microglia isolated from the brains after treatment. Taken together, our results show that LPSp holds promise as a preventative therapy for AD or AD-related diseases induced by impairment of metabolic functions.

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“…This possibility is supported by convincing evidence that hsps can induce immunoregulatory T cell responses [24–27]. The immunomodulatory ability of the mycobacterial hsp65 in autoimmune diseases has been demonstrated by us and other authors in arthritis [28, 29], diabetes [30–32], and atherosclerosis [27, 33]. …”

Section: Introductionmentioning

confidence: 74%

pVAXhsp65 Vaccination Primes for High IL-10 Production and Decreases Experimental Encephalomyelitis Severity

Zorzella-Pezavento

Chiuso-Minicucci

França

et al. 2017

Journal of Immunology Research

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Experimental autoimmune encephalomyelitis (EAE) is a demyelinating pathology of the central nervous system (CNS) used as a model to study multiple sclerosis immunopathology. EAE has also been extensively employed to evaluate potentially therapeutic schemes. Considering the presence of an immune response directed to heat shock proteins (hsps) in autoimmune diseases and the immunoregulatory potential of these molecules, we evaluated the effect of a previous immunization with a genetic vaccine containing the mycobacterial hsp65 gene on EAE development. C57BL/6 mice were immunized with 4 pVAXhsp65 doses and 14 days later were submitted to EAE induction by immunization with myelin oligodendrocyte glycoprotein (MOG35–55) emulsified in Complete Freund's Adjuvant. Vaccinated mice presented significant lower clinical scores and lost less body weight. MOG35–55 immunization also determined less inflammation in lumbar spinal cord but did not change CD4+CD25+Foxp3+ T cells frequency in spleen and CNS. Infiltrating cells from the CNS stimulated with rhsp65 produced significantly higher levels of IL-10. These results suggest that the ability of pVAXhsp65 vaccination to control EAE development is associated with IL-10 induction.

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Mycobacterial heat shock protein 65 (mbHSP65)-induced atherosclerosis: Preventive oral tolerization and definition of atheroprotective and atherogenic mbHSP65 peptides

Cited by 32 publications

References 34 publications

Oral administration of Pantoea agglomerans-derived lipopolysaccharide prevents development of atherosclerosis in high-fat diet-fed apoE-deficient mice via ameliorating hyperlipidemia, pro-inflammatory mediators and oxidative responses

Oral administration of Pantoea agglomerans-derived lipopolysaccharide prevents development of atherosclerosis in high-fat diet-fed apoE-deficient mice via ameliorating hyperlipidemia, pro-inflammatory mediators and oxidative responses

Oral administration of Pantoea agglomerans-derived lipopolysaccharide prevents metabolic dysfunction and Alzheimer’s disease-related memory loss in senescence-accelerated prone 8 (SAMP8) mice fed a high-fat diet

pVAXhsp65 Vaccination Primes for High IL-10 Production and Decreases Experimental Encephalomyelitis Severity

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