<i>Enterococcus faecalis</i> shifts macrophage polarization toward M1-like phenotype with an altered cytokine profile

Elashiry, Mohamed M.; Tian, Fucong; Elashiry, Mahmoud; Zeitoun, Rana; Elsayed, Ranya; Andrews, Matthew L.; Bergeon, Brian E.; Cutler, Christopher W.; Tay, Franklin R.

doi:10.1080/20002297.2020.1868152

Cited by 12 publications

(10 citation statements)

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“…In a study by Zou et al, 1 h of E. faecalis E99 strain (a clinical isolate from the urine of a patient) infection at an MOI of 10:1 prevented apoptosis in macrophages subjected to a wide spectrum of proapoptotic stimuli (Zou and Shankar, 2014). In Mohamed Elashiry et al's study, a low E. faecalis MOI (1:1) in bone marrow stem cells (BMSCs) for a prolonged time reduced the apoptotic activity in subsequently differentiated macrophages (Mohamed Elashiry et al, 2021) results of the two studies indicate that E. faecalis at low MOIs represses apoptosis of macrophages and decreases apoptotic cell deaths to facilitate a continuous infection. Similarly, we found no PI-positive macrophages before 5 h of infection in our study, indicating the absence of dead cells.…”

Section: Discussionmentioning

confidence: 99%

Real-Time Induction of Macrophage Apoptosis, Pyroptosis, and Necroptosis by Enterococcus faecalis OG1RF and Two Root Canal Isolated Strains

Chi

Lin

Meng

et al. 2021

Front. Cell. Infect. Microbiol.

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To investigate the effects of two Enterococcus faecalis root canal isolated strains (CA1 and CA2) and of the OG1RF strain on apoptosis, pyroptosis, and necroptosis in macrophages. The virulence factors of E. faecalis CA1 and CA2 pathogenic strains were annotated in the Virulence Factors Database (VFDB). E. faecalis CA1, CA2, and OG1RF strains were used to infect RAW264.7 macrophages (MOI, 100:1). We assessed the viability of intracellular and extracellular bacteria and of macrophages at 2, 6, and 12 h post-infection. We used a live cell imaging analysis system to obtain a dynamic curve of cell death after infection by each of the three E. faecalis strains. At 6 and 12 h post-infection, we quantified the mRNA expression levels of PANoptosis-related genes and proteins by RT-qPCR and western blot, respectively. We identified ultrastructural changes in RAW264.7 cells infected with E. faecalis OG1RF using transmission electron microscopy. We found 145 and 160 virulence factors in the CA1 and CA2 strains, respectively. The extracellular CA1 strains grew faster than the CA2 and OG1RF strains, and the amount of intracellular viable bacteria in the OG1RF group was highest at 6 and 12 h post-infection. The macrophages in the CA1 infection group were the first to reach the maximum PI-positivity in the cell death time point curve. We found the expressions of mRNA expression of caspase-1, GSDMD, caspase-3, MLKL, RIPK3, NLRP3, IL-1β and IL-18 and of proteins cleaved caspase-1, GSDMD, cleaved caspase-3 and pMIKL in the macrophages of the three infection groups to be upregulated (P<0.05). We detected ultrastructural changes of apoptosis, pyroptosis, and necroptosis in macrophages infected with E. faecalis. The three E. faecalis strains induced varying degrees of apoptosis, pyroptosis, and necroptosis that were probably associated with PANoptosis in macrophages. The E. faecalis CA1 strain exhibited faster growth and a higher real-time MOI, and it induced higher expression levels of some PANoptosis-related genes and proteins in the infected macrophages than the other strains tested.

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Section: Discussionmentioning

confidence: 99%

Real-Time Induction of Macrophage Apoptosis, Pyroptosis, and Necroptosis by Enterococcus faecalis OG1RF and Two Root Canal Isolated Strains

Chi

Lin

Meng

et al. 2021

Front. Cell. Infect. Microbiol.

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“…LTA of E. faecalis increases the expression of NLRP3 and caspase-1 via upregulation of ROS and activation of NF-κB in RAW264.7 cells, and this effect can be reversed by inhibitors of NLRP3 or NF-κB ( 146 , 265 ). Moreover, E. faecalis infection triggers atypical M1-like macrophage polarization in murine bone marrow-derived stem cells; however, the roles of inflammasomes in this process remain unclear ( 266 ). LPS from P. gingivalis increases the mRNA levels of NLRP3 , AIM2 , ASC , and caspase-1 in THP-1 macrophages ( 183 ).…”

Section: Inflammasomes In Inflammatory Osteolysis Of the Alveolar Bone And Jawsmentioning

confidence: 99%

Inflammasomes in Alveolar Bone Loss

Ling

Jiang

2021

Front. Immunol.

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Bone remodeling is tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Fine tuning of the osteoclast–osteoblast balance results in strict synchronization of bone resorption and formation, which maintains structural integrity and bone tissue homeostasis; in contrast, dysregulated bone remodeling may cause pathological osteolysis, in which inflammation plays a vital role in promoting bone destruction. The alveolar bone presents high turnover rate, complex associations with the tooth and periodontium, and susceptibility to oral pathogenic insults and mechanical stress, which enhance its complexity in host defense and bone remodeling. Alveolar bone loss is also involved in systemic bone destruction and is affected by medication or systemic pathological factors. Therefore, it is essential to investigate the osteoimmunological mechanisms involved in the dysregulation of alveolar bone remodeling. The inflammasome is a supramolecular protein complex assembled in response to pattern recognition receptors and damage-associated molecular patterns, leading to the maturation and secretion of pro-inflammatory cytokines and activation of inflammatory responses. Pyroptosis downstream of inflammasome activation also facilitates the clearance of intracellular pathogens and irritants. However, inadequate or excessive activity of the inflammasome may allow for persistent infection and infection spreading or uncontrolled destruction of the alveolar bone, as commonly observed in periodontitis, periapical periodontitis, peri-implantitis, orthodontic tooth movement, medication-related osteonecrosis of the jaw, nonsterile or sterile osteomyelitis of the jaw, and osteoporosis. In this review, we present a framework for understanding the role and mechanism of canonical and noncanonical inflammasomes in the pathogenesis and development of etiologically diverse diseases associated with alveolar bone loss. Inappropriate inflammasome activation may drive alveolar osteolysis by regulating cellular players, including osteoclasts, osteoblasts, osteocytes, periodontal ligament cells, macrophages, monocytes, neutrophils, and adaptive immune cells, such as T helper 17 cells, causing increased osteoclast activity, decreased osteoblast activity, and enhanced periodontium inflammation by creating a pro-inflammatory milieu in a context- and cell type-dependent manner. We also discuss promising therapeutic strategies targeting inappropriate inflammasome activity in the treatment of alveolar bone loss. Novel strategies for inhibiting inflammasome signaling may facilitate the development of versatile drugs that carefully balance the beneficial contributions of inflammasomes to host defense.

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“…Lipopolysaccharide (LPS) is one of the most well-studied PAMPs in diabetes and has been found to disturb the hematopoietic balance [ 34 , 35 ]. LPS administration drives quiescent LT-HSCs into the cell cycle and promotes the differentiation of HSPCs towards a more proinflammatory cell type, possibly via the direct activation of Toll-like receptor 4 on the cell surface [ 36 , 37 ]. On the other hand, LPS acts on nonhematopoietic cells, such as endothelial cells and mesenchymal stromal cells, and promotes the secretion of proinflammatory cytokines in the hematopoietic microenvironment, which indirectly affects HSPCs by engineering the bone marrow niche [ 38 – 41 ].…”

Section: Discussionmentioning

confidence: 99%

Peptidoglycan-Mediated Bone Marrow Autonomic Neuropathy Impairs Hematopoietic Stem/Progenitor Cells via a NOD1-Dependent Pathway in db/db Mice

Zhang

et al. 2022

Stem Cells International

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Impairment of bone marrow-derived hematopoietic stem/progenitor cells (HSPCs) contributes to the progression of vascular complications in subjects with diabetes. Very small amounts of bacterial-derived pathogen-associated molecular patterns (PAMPs) establish the bone marrow cell pool. We hypothesize that alteration of the PAMP peptidoglycan (PGN) exacerbates HSPC dysfunction in diabetes. We observed increased PGN infiltration in the bone marrow of diabetic mice. Exogenous administration of PGN selectively reduced the number of long-term repopulating hematopoietic stem cells (LT-HSCs), accompanied by impaired vasoreparative functions in db/db mouse bone marrow. We further revealed that bone marrow denervation contributed to PGN-associated HSPC dysfunction. Inhibition of NOD1 ameliorated PGN-induced bone marrow autonomic neuropathy, which significantly rejuvenated the HSPC pools and functions in vivo. These data reveal for the first time that PGN, as a critical factor on the gut-bone marrow axis, promotes bone marrow denervation and HSPC modulation in the context of diabetes.

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Enterococcus faecalis shifts macrophage polarization toward M1-like phenotype with an altered cytokine profile

Cited by 12 publications

References 50 publications

Real-Time Induction of Macrophage Apoptosis, Pyroptosis, and Necroptosis by Enterococcus faecalis OG1RF and Two Root Canal Isolated Strains

Real-Time Induction of Macrophage Apoptosis, Pyroptosis, and Necroptosis by Enterococcus faecalis OG1RF and Two Root Canal Isolated Strains

Inflammasomes in Alveolar Bone Loss

Peptidoglycan-Mediated Bone Marrow Autonomic Neuropathy Impairs Hematopoietic Stem/Progenitor Cells via a NOD1-Dependent Pathway in db/db Mice

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