Effects of Aging on Endotoxin Tolerance Induced by Lipopolysaccharides Derived from Porphyromonas gingivalis and Escherichia coli

Sun, Ying; Li, Hui; Yang, Mingxia; Shu, Wei; Sun, Mengjun; Xu, Yan

doi:10.1371/journal.pone.0039224

Cited by 40 publications

(38 citation statements)

References 54 publications

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“…Notably, previous reports investigating whether P. gingivalis LPS interferes with the activity of E. coli LPS provide different molecular explanations: they support the hypothesis that the inhibitory potential was attributable either to tolerance mediated by loss of the ability to upregulate TLR2 or TLR4 expression upon restimulation with E. coli or P. gingivalis LPS (33,47) or, alternatively, to TLR4 antagonism mediated via direct interaction of P. gingivalis LPS with TLR4 (42,43). In addition, dephosphorylation of lipid A by P. gingivalis phosphatases prevents TLR4 activation and promotes resistance to cationic antimicrobial peptides (48).…”

Section: Discussionmentioning

confidence: 87%

Porphyromonas gingivalis Outer Membrane Vesicles Induce Selective Tumor Necrosis Factor Tolerance in a Toll-Like Receptor 4- and mTOR-Dependent Manner

et al. 2016

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f Porphyromonas gingivalis is an important member of the anaerobic oral flora. Its presence fosters growth of periodontal biofilm and development of periodontitis. In this study, we demonstrated that lipophilic outer membrane vesicles (OMV) shed from P. gingivalis promote monocyte unresponsiveness to live P. gingivalis but retain reactivity to stimulation with bacterial DNA isolated from P. gingivalis or AIM2 ligand poly(dA·dT). OMV-mediated tolerance of P. gingivalis is characterized by selective abrogation of tumor necrosis factor (TNF). Neutralization of interleukin-10 (IL-10) during OMV challenge partially restores monocyte responsiveness to P. gingivalis; full reactivity to P. gingivalis can be restored by inhibition of mTOR signaling, which we previously identified as the major signaling pathway promoting Toll-like receptor 2 and Toll-like receptor 4 (TLR2/4)-mediated tolerance in monocytes. However, despite previous reports emphasizing a central role of TLR2 in innate immune recognition of P. gingivalis, our current findings highlight a selective role of TLR4 in the promotion of OMV-mediated TNF tolerance: only blockade of TLR4 -and not of TLR2-restores responsiveness to P. gingivalis. Of further note, OMV-mediated tolerance is preserved in the presence of cytochalasin B and chloroquine, indicating that triggering of surface TLR4 is sufficient for this effect. Taking the results together, we propose that P. gingivalis OMV contribute to local immune evasion of P. gingivalis by hampering the host response. P eriodontitis (PD) is probably the most frequent chronic inflammatory disorder associated with an alteration of the local microbiota. Clinically, release of inflammatory mediators induces collagen degradation and bone resorption, which ultimately result in tooth loss. The carbohydrate-deficient subgingival environment fosters the growth of Porphyromonas gingivalis (1). Tissue degradation caused by enzymes released from bacteria and neutrophils provokes an inflammatory response and supplies bacteria with additional nutrients. This specific milieu permits growth of P. gingivalis, whose sophisticated mechanisms for immune evasion enhance growth of the periodontal biofilm, thus leading to bacterial overgrowth and excessive immune stimulation (2, 3).P. gingivalis releases outer membrane lipophilic microvesicles, which contain lipopolysaccharide (LPS) as a major structural component (4-6). These outer membrane vesicles (OMV) overcome the epithelial barrier, thus transporting LPS and other virulence factors into the host tissue (7). Subsequently, OMV elicit a robust mucosal immune response (8), an effect exploited in OMV-based vaccines (8, 9) and mainly attributed to their LPS content (6). However, unlike LPS from Escherichia coli or Salmonella spp., which are Toll-like receptor 4 (TLR4) agonists, P. gingivalis LPS contains a mixture of chemically diverse lipid A species with distinct immune stimulatory properties (10). Albeit P. gingivalis LPS was formerly thought to act as a TLR2 ligand (11, 12), recent studi...

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Section: Discussionmentioning

confidence: 87%

Porphyromonas gingivalis Outer Membrane Vesicles Induce Selective Tumor Necrosis Factor Tolerance in a Toll-Like Receptor 4- and mTOR-Dependent Manner

et al. 2016

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“…Repeated exposure to LPS induces endotoxin tolerance, which is associated with reduced inflammatory cytokine production (50). For example, Sun and colleagues demonstrated that pretreatment of macrophages with E. coli LPS decreased tumor necrosis factor-a production from 1,700 to 100 pg/ml (51). Similar effects were observed in vivo (52).…”

Section: Discussionmentioning

confidence: 87%

Bone Morphogenetic Protein Receptor Type II Deficiency and Increased Inflammatory Cytokine Production. A Gateway to Pulmonary Arterial Hypertension

Soon

Crosby

Southwood

et al. 2015

Am J Respir Crit Care Med

122

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Rationale: Mutations in bone morphogenetic protein receptor type II (BMPR-II) underlie most cases of heritable pulmonary arterial hypertension (PAH). However, disease penetrance is only 20-30%, suggesting a requirement for additional triggers. Inflammation is emerging as a key disease-related factor in PAH, but to date there is no clear mechanism linking BMPR-II deficiency and inflammation.Objectives: To establish a direct link between BMPR-II deficiency, a consequentially heightened inflammatory response, and development of PAH.Methods: We used pulmonary artery smooth muscle cells from Bmpr2 1/2 mice and patients with BMPR2 mutations and compared them with wild-type controls. For the in vivo model, we used mice heterozygous for a null allele in Bmpr2 (Bmpr2 1/2) and wild-type littermates.Measurements and Main Results: Acute exposure to LPS increased lung and circulating IL-6 and KC (IL-8 analog) levels in Bmpr21/2 mice to a greater extent than in wild-type controls. Similarly, pulmonary artery smooth muscle cells from Bmpr2 1/2 mice and patients with BMPR2 mutations produced higher levels of IL-6 and KC/IL-8 after lipopolysaccharide stimulation compared with controls. BMPR-II deficiency in mouse and human pulmonary artery smooth muscle cells was associated with increased phospho-STAT3 and loss of extracellular superoxide dismutase. Chronic lipopolysaccharide administration caused pulmonary hypertension in Bmpr2 1/2 mice but not in wild-type littermates. Coadministration of tempol, a superoxide dismutase mimetic, ameliorated the exaggerated inflammatory response and prevented development of PAH.Conclusions: This study demonstrates that BMPR-II deficiency promotes an exaggerated inflammatory response in vitro and in vivo, which can instigate development of pulmonary hypertension.

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“…This could cause extensive microvascular angiopathy in advanced periodontitis, and could also explain the attenuation of the inflammatory reaction in periodontal tissue [38]. Besides, repeated LPS stimulation or degradation of CD14 receptors (the main receptor for bacterial cell surface components such as LPS) on the surface of human macrophage-like cells by gingipains of P. gingivalis result in hyporesponsiveness of macrophages to LPS stimulation, and may contribute to an increased capacity of P. gingivalis and other periodontopathogens to evade host immune system mechanisms [39,40], resulting in chronic inflammation [41], which may also entail decreased count of WBC in GMB in periodontitis patients. Decreased counts of WBC in GMB of these patients may be influenced by an increased coagulation in vasculature of periodontal tissue via the degradation and inactivation of endothelial thrombomodulin by gingipains of P. gingivalis, resulting in local consumption of WBC [42].…”

Section: Discussionmentioning

confidence: 99%

Local and systemic immune responses in gingivitis and periodontitis

et al. 2014

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Effects of Aging on Endotoxin Tolerance Induced by Lipopolysaccharides Derived from Porphyromonas gingivalis and Escherichia coli

Cited by 40 publications

References 54 publications

Porphyromonas gingivalis Outer Membrane Vesicles Induce Selective Tumor Necrosis Factor Tolerance in a Toll-Like Receptor 4- and mTOR-Dependent Manner

Porphyromonas gingivalis Outer Membrane Vesicles Induce Selective Tumor Necrosis Factor Tolerance in a Toll-Like Receptor 4- and mTOR-Dependent Manner

Bone Morphogenetic Protein Receptor Type II Deficiency and Increased Inflammatory Cytokine Production. A Gateway to Pulmonary Arterial Hypertension

Local and systemic immune responses in gingivitis and periodontitis

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