Human β-defensin-3 alleviates the progression of atherosclerosis accelerated by Porphyromonas gingivalis lipopolysaccharide

Li, Lili; Bian, Tianying; Lyu, Jinglu; Cui, Di; Lei, Lang; Yan, Fuhua

doi:10.1016/j.intimp.2016.06.003

Cited by 13 publications

(13 citation statements)

References 46 publications

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“…Fos proteins are regulated by various stimuli like cytokines and growth factors, dependent on MAPK pathways ( 44 ). Previous studies revealed that BD3 reduces the phosphorylation of p38 and c-Jun MAPK pathway in human umbilical vein endothelial cells ( 45 ). Bian and colleagues have recently found that BD3 is involved in the attenuation of the phosphorylation of p38 and ERK1/2 in MAPK pathway ( 13 ).…”

Section: Discussionmentioning

confidence: 99%

Beta-Defensin 2 and 3 Promote Bacterial Clearance of Pseudomonas aeruginosa by Inhibiting Macrophage Autophagy through Downregulation of Early Growth Response Gene-1 and c-FOS

Wang

et al. 2018

Front. Immunol.

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Beta-defensins 2 and 3 (BD2 and BD3) are inducible peptides present at the sites of infection, and they are well characterized for their antimicrobial activities and immune-regulatory functions. However, no study has thoroughly investigated their immunomodulatory effects on macrophage-mediated immune responses against Pseudomonas aeruginosa (PA). Here, we use THP-1 and RAW264.7 cell lines and demonstrate that BD2 and BD3 suppressed macrophage autophagy but enhanced the engulfment of PA and Zymosan bioparticles as well as the formation of phagolysosomes, using immunofluorescence staining and confocal microscopy. Plate count assay showed that macrophage-mediated phagocytosis and intracellular killing of PA were promoted by BD2 and BD3. Furthermore, microarray and real-time PCR showed that the expression of two genes, early growth response gene-1 (EGR1) and c-FOS, was attenuated by BD2 and BD3. Western blot revealed that BD2 and BD3 inhibited the expression and nuclear translocation of EGR1 and c-FOS. Knockdown of EGR1 and c-FOS by siRNA transfection suppressed macrophage autophagy before and after PA infection; while overexpression of these two transcription factors enhanced autophagy but reversed the role of BD2 and BD3 on macrophage-mediated PA eradication. Together, these results demonstrate a novel immune defense activity of BD2 and BD3, which promotes clearance of PA by inhibiting macrophage autophagy through downregulation of EGR1 and c-FOS.

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Section: Discussionmentioning

confidence: 99%

Beta-Defensin 2 and 3 Promote Bacterial Clearance of Pseudomonas aeruginosa by Inhibiting Macrophage Autophagy through Downregulation of Early Growth Response Gene-1 and c-FOS

Wang

et al. 2018

Front. Immunol.

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“…Pg is a gram negative bacterium associated with the pathogenesis of periodontitis 50 . Periodontitis has been linked to numerous low-grade inflammatory diseases, such as obesity 51 , 52 , atherosclerosis 11 , 12 , 15 , and neuroinflammatory diseases (Alzheimer’s) 53 – 55 . LPSs are the major inflammatory mediators for gram negative bacteria.…”

Section: Discussionmentioning

confidence: 99%

“…Atherosclerosis is a multifactorial disease. Infection by P. gingivalis (whole bacteria or derived-products such as LPS or heat-shock proteins) has been identified as an important factor leading to an inflammatory response from endothelial cells and other cells of the vascular wall 11 , 12 . LPS from P. gingivalis ( Pg LPS) is able to stimulate proinflammatory cytokine secretion leading to the recruitment of monocytes/macrophages into atherosclerotic plaques 13 – 17 .…”

Section: Introductionmentioning

confidence: 99%

Porphyromonas gingivalis lipopolysaccharides act exclusively through TLR4 with a resilience between mouse and human

Nativel¹,

Couret²,

Giraud³

et al. 2017

Sci Rep

105

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Porphyromonas gingivalis is a key bacterium in chronic periodontitis, which is associated with several chronic inflammatory diseases. Lipopolysaccharides from P. gingivalis (Pg LPS) can activate multiple cell types via the production of pro-inflammatory cytokines. The receptors for Pg LPS have initially been reported as TLR2, contrasting with the well-studied TLR4 receptor for E. coli LPS; this observation remains controversial since synthetic Pg lipid A activates TLR4 but not TLR2. Despite this observation, the dogma of Pg LPS-mediated TLR2 activation remains the basis of many hypotheses and result interpretations. In the present work, we aimed at determining whether TLR4 or TLR2, or both, mediate Pg LPS pro-inflammatory activity using Pg LPS with different grades of purity, instead of synthetic lipid A from Pg LPS. Here we show that Pg LPS 1) acts exclusively through TLR4, and 2) are differently recognized by mouse and human TLR4 both in vitro and in vivo. Taken together, our results suggest that Pg LPS activity is mediated exclusively through TLR4 and only weakly induces proinflammatory cytokine secretion in mouse models. Caution should be taken when extrapolating data from mouse systems exposed to Pg or Pg LPS to humans.

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“…The upregulation of hBD3 by TNF- α in HUVECs illustrates the important role that defensins play in host immune defense against inflammation. In our previous study, we demonstrated that hBD3 strongly inhibited the progression of early-stage atherosclerotic lesions and inflammation levels in RAW 264.7 cells and human THP-1-derived macrophages [16, 17]. …”

Section: Introductionmentioning

confidence: 99%

Humanβ-Defensin 3 Reduces TNF-α-Induced Inflammation and Monocyte Adhesion in Human Umbilical Vein Endothelial Cells

Bian

Zhou

et al. 2017

Mediators of Inflammation

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The aim of this study was to investigate the role of human β-defensin 3 (hBD3) in the initiation stage of atherosclerosis with human umbilical vein endothelial cells (HUVECs) triggered by tumor necrosis factor- (TNF-) α. The effects of hBD3 on TNF-α-induced endothelial injury and inflammatory response were evaluated. Our data revealed that first, hBD3 reduced the production of interleukin-6 (IL-6), IL-8, monocyte chemoattractant protein-1 (MCP-1), and macrophage migration inhibitory factor (MIF) in HUVECs in a dose-dependent manner. In addition, hBD3 significantly prevented intracellular reactive oxygen species (ROS) production by HUVECs. Second, western blot analysis demonstrated that hBD3 dose-dependently suppressed the protein levels of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in TNF-α-induced HUVECs. As a result, hBD3 inhibited monocyte adhesion to TNF-α-treated endothelial cells. Additionally, hBD3 suppressed TNF-α-induced F-actin reorganization in HUVECs. Third, hBD3 markedly inhibited NF-κB activation by decreasing the phosphorylation of IKK-α/β, IκB, and p65 subunit within 30 min. Moreover, the phosphorylation of p38 and c-Jun N-terminal protein kinase (JNK) in the mitogen-activated protein kinase (MAPK) pathway were also inhibited by hBD3 in HUVECs. In conclusion, hBD3 exerts anti-inflammatory and antioxidative effects in endothelial cells in response to TNF-α by inhibiting NF-κB and MAPK signaling.

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Human β-defensin-3 alleviates the progression of atherosclerosis accelerated by Porphyromonas gingivalis lipopolysaccharide

Cited by 13 publications

References 46 publications

Beta-Defensin 2 and 3 Promote Bacterial Clearance of Pseudomonas aeruginosa by Inhibiting Macrophage Autophagy through Downregulation of Early Growth Response Gene-1 and c-FOS

Beta-Defensin 2 and 3 Promote Bacterial Clearance of Pseudomonas aeruginosa by Inhibiting Macrophage Autophagy through Downregulation of Early Growth Response Gene-1 and c-FOS

Porphyromonas gingivalis lipopolysaccharides act exclusively through TLR4 with a resilience between mouse and human

Humanβ-Defensin 3 Reduces TNF-α-Induced Inflammation and Monocyte Adhesion in Human Umbilical Vein Endothelial Cells

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