scholarly journals Intracellular and Extracellular Lipopolysaccharide Signaling in Sepsis: Avenues for Novel Therapeutic Strategies

2021 ◽  
pp. 1-10
Author(s):  
Ramy S. Gabarin ◽  
Manshu Li ◽  
Paige A. Zimmel ◽  
John C. Marshall ◽  
Yimin Li ◽  
...  
Keyword(s):  
Purinergic Receptor ◽  
Host Cells ◽  
Toll Like Receptor 4 ◽  
Pyrin Domain ◽  
Downstream Effectors ◽  
Promising Therapeutic Approach ◽  
Novel Therapeutic Strategies ◽  
Lps Signaling ◽  
Major Mediator ◽  
Lps Binding

Sepsis is defined as organ dysfunction due to a dysregulated systemic host response to infection. During gram-negative bacterial infection and other acute illness such as absorption from the gut infection, lipopolysaccharide (LPS) is a major mediator in sepsis. LPS is able to trigger inflammation through both intracellular and extracellular pathways. Classical interactions between LPS and host cells first involve LPS binding to LPS binding protein (LBP), a carrier. The LPS-LBP complex then binds to a receptor complex including the CD14, MD2, and toll-like receptor 4 (TLR4) proteins, initiating a signal cascade which triggers the secretion of pro-inflammatory cytokines. However, it has been established that LPS is also internalized by macrophages and endothelial cells through TLR4-independent pathways. Once internalized, LPS is able to bind to the cytosolic receptors caspases-4/5 in humans and the homologous caspase-11 in mice. Bound caspases-4/5 oligomerize and trigger the assembly of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome followed by the activation of inflammatory caspase-1 resulting in subsequent release of interleukin-1β. Caspases-4/5 also activate the perforin gasdermin D and purinergic receptor P2X7, inducing cell lysis and pyroptosis. Pyroptosis is a notable source of inflammation and damage to the lung endothelial barrier during sepsis. Thus, inhibition of caspases-4/5/1 or downstream effectors to block intracellular LPS signaling may be a promising therapeutic approach in adjunction with neutralizing extracellular LPS for treatment of sepsis.

scholarly journals Components of the endocytic and recycling trafficking pathways interfere with the integrity of the Legionella-containing vacuole

2019 ◽  
Author(s):  
Ila S. Anand ◽  
Won Young Choi ◽  
Ralph R. Isberg
Keyword(s):  
Membrane Trafficking ◽  
Legionella Pneumophila ◽  
Host Cells ◽  
Rab Gtpases ◽  
Intracellular Growth ◽  
Mutant Proteins ◽  
Host Cytoplasm ◽  
Downstream Effectors ◽  
Cell Death Response ◽  
Host Membrane

SummaryLegionella pneumophila requires the Dot/Icm translocation system to replicate in a vacuolar compartment within host cells. Strains lacking the translocated substrate SdhA form a permeable vacuole during residence in the host cell, exposing bacteria to the host cytoplasm. In primary macrophages, mutants are defective for intracellular growth, with a pyroptotic cell death response mounted due to bacterial exposure to the cytosol. To understand how SdhA maintains vacuole integrity during intracellular growth, we performed high-throughput RNAi screens against host membrane trafficking genes to identify factors that antagonize vacuole integrity in the absence of SdhA. Depletion of host proteins involved in endocytic uptake and recycling resulted in enhanced intracellular growth and lower levels of permeable vacuoles surrounding the ΔsdhA mutant. Of interest were three different Rab GTPases involved in these processes: Rab11b, Rab8b and Rab5 isoforms, that when depleted resulted in enhanced vacuole integrity surrounding the sdhA mutant. Proteins regulated by these Rabs are responsible for interfering with proper vacuole membrane maintenance, as depletion of the downstream effectors EEA1, Rab11FIP1, or VAMP3 rescued vacuole integrity and intracellular growth of the sdhA mutant. To test the model that specific vesicular components associated with these effectors could act to destabilize the replication vacuole, EEA1 and Rab11FIP1 showed enhanced colocalization with the vacuole surrounding the sdhA mutant compared with the WT vacuole. Depletion of Rab5 isoforms or Rab11b reduced this aberrant colocalization. These findings are consistent with SdhA interfering with both endocytic and recycling membrane trafficking events that act to destabilize vacuole integrity during infection.

scholarly journals Toll-Like Receptor 4 Signaling and Drug Addiction

2020 ◽  
Vol 11 ◽  
Author(s):  
Ruyan Wu ◽  
Jun-Xu Li
Keyword(s):  
Drug Addiction ◽  
Multiple Drug ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling ◽  
Drug Classes ◽  
Downstream Effectors ◽  
Potential Efficacy ◽  
Proinflammatory Responses

The emphasis of neuronal alterations and adaptations have long been the main focus of the studies of the mechanistic underpinnings of drug addiction. Recent studies have begun to appreciate the role of innate immune system, especially toll-like receptor 4 (TLR4) signaling in drug reward-associated behaviors and physiology. Drugs like opioids, alcohol and psychostimulants activate TLR4 signaling and subsequently induce proinflammatory responses, which in turn contributes to the development of drug addiction. Inhibition of TLR4 or its downstream effectors attenuated the reinforcing effects of opioids, alcohol and psychostimulants, and this effect is also involved in the withdrawal and relapse-like behaviors of different drug classes. However, conflicting results also argue that TLR4-related immune response may play a minimal part in drug addiction. This review discussed the preclinical evidence that whether TLR4 signaling is involved in multiple drug classes action and the possible mechanisms underlying this effect. Moreover, clinical studies which examined the potential efficacy of immune-base pharmacotherapies in treating drug addiction are also discussed.

Exploring the LPS/TLR4 signal pathway with small molecules

2010 ◽  
Vol 38 (5) ◽  
pp. 1390-1395 ◽  
Author(s):  
Francesco Peri ◽  
Matteo Piazza ◽  
Valentina Calabrese ◽  
Gaetana Damore ◽  
Roberto Cighetti
Keyword(s):  
Innate Immunity ◽  
Small Molecules ◽  
Innate Immune ◽  
Toll Like Receptor 4 ◽  
Innate Immunity Cells ◽  
Specific Receptors ◽  
Extracellular Side ◽  
Tlr4 Activation ◽  
Lps Binding

The identification of the bacterial endotoxin receptors for innate immunity, most notably TLR4 (Toll-like receptor 4), has sparked great interest in therapeutic manipulation of the innate immune system. In the present mini-review, several natural and synthetic molecules that modulate the TLR4-mediated LPS (lipopolysaccharide) signalling in animals and humans are considered, and their mechanisms of action are discussed. The process of LPS sensing and signal amplification in humans is based on the sequential action of specific receptors situated in the extracellular side of the innate immunity cells, which bind and transfer LPS to TLR4: LBP (LPS-binding protein), CD14, MD-2 (myeloid differentiation protein 2). We classified the compounds active on TLR4 pathway depending on the specific molecular targets (LPS, LBP, CD14, MD-2 or TLR4). Small molecules developed by our group are described that inhibit LPS-stimulated TLR4 activation by selectively targeting the LPS–CD14 interaction. These compounds have an interesting antiseptic shock, anti-inflammatory and anti-neuropathic pain activity in vivo.

Hemorrhagic shock recruits Toll-like receptor 4 to the plasma membrane in macrophages: A novel mechanism of cell priming for LPS signaling

2005 ◽  
Vol 201 (3) ◽  
pp. S36
Author(s):  
Kinga A. Powers ◽  
Katalin Szaszi ◽  
Rachel Khadaroo ◽  
Patrick Tawadros ◽  
John C. Marshall ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Hemorrhagic Shock ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Lps Signaling

scholarly journals Role of Host Type IA Phosphoinositide 3-Kinase Pathway Components in Invasin-Mediated Internalization of Yersinia enterocolitica

2016 ◽  
Vol 84 (6) ◽  
pp. 1826-1841 ◽  
Author(s):  
Georgina C. Dowd ◽  
Manmeet Bhalla ◽  
Bernard Kean ◽  
Rowan Thomas ◽  
Keith Ireton
Keyword(s):  
Actin Cytoskeleton ◽  
Yersinia Enterocolitica ◽  
Pi3k Pathway ◽  
Host Cells ◽  
Content Type ◽  
Downstream Effectors ◽  
Food Borne ◽  
Type Ia ◽  
Human Proteins ◽  
Phosphoinositide 3 Kinase

Many bacterial pathogens subvert mammalian type IA phosphoinositide 3-kinase (PI3K) in order to induce their internalization into host cells. How PI3K promotes internalization is not well understood. Also unclear is whether type IA PI3K affects different pathogens through similar or distinct mechanisms. Here, we performed an RNA interference (RNAi)-based screen to identify components of the type IA PI3K pathway involved in invasin-mediated entry ofYersinia enterocolitica, an enteropathogen that causes enteritis and lymphadenitis. The 69 genes targeted encode known upstream regulators or downstream effectors of PI3K. A similar RNAi screen was previously performed with the food-borne bacteriumListeria monocytogenes. The results of the screen withY. enterocoliticaindicate that at least nine members of the PI3K pathway are needed for invasin-mediated entry. Several of these proteins, including centaurin-α1, Dock180, focal adhesion kinase (FAK), Grp1, LL5α, LL5β, and PLD2 (phospholipase D2), were recruited to sites of entry. In addition, centaurin-α1, FAK, PLD2, and mTOR were required for remodeling of the actin cytoskeleton during entry. Six of the human proteins affecting invasin-dependent internalization also promote InlB-mediated entry ofL. monocytogenes. Our results identify several host proteins that mediate invasin-induced effects on the actin cytoskeleton and indicate that a subset of PI3K pathway components promote internalization of bothY. enterocoliticaandL. monocytogenes.

Heterotrimeric Gi/Go proteins modulate endothelial TLR signaling independent of the MyD88-dependent pathway

2011 ◽  
Vol 301 (6) ◽  
pp. H2246-H2253 ◽  
Author(s):  
Shauna M. Dauphinee ◽  
Verena Voelcker ◽  
Zinaida Tebaykina ◽  
Fred Wong ◽  
Aly Karsan
Keyword(s):  
G Proteins ◽  
Interleukin 1 ◽  
Tumor Necrosis Factor Receptor ◽  
Signaling Cascade ◽  
Immune Recognition ◽  
Heterotrimeric G Proteins ◽  
Interferon Signaling ◽  
Toll Like Receptor 4 ◽  
Lps Signaling ◽  
Necrosis Factor

The innate immune recognition of bacterial lipopolysaccharide (LPS) is mediated by Toll-like receptor 4 (TLR4) and results in activation of proinflammatory signaling including NF-κB and MAPK pathways. Heterotrimeric G proteins have been previously implicated in LPS signaling in macrophages and monocytes. In the present study, we show that pertussis toxin sensitive heterotrimeric G proteins (Gαi/o) are involved in the activation of MAPK and Akt downstream of TLR2, TLR3, and TLR4 in endothelial cells. Gαi/o are also required for full activation of interferon signaling downstream of TLR3 and TLR4 but are not required for the activation of NF-κB. We find that Gαi/o-mediated activation of the MAPK is independent of the canonical MyD88, interleukin-1 receptor-associated kinase, and tumor necrosis factor receptor-associated factor 6 signaling cascade in LPS-stimulated cells. Taken together, the data presented here suggest that heterotrimeric G proteins are widely involved in TLR pathways along a signaling cascade that is distinct from MyD88-TRAF6.

scholarly journals C-Terminal Amination of a Cationic Anti-Inflammatory Peptide Improves Bioavailability and Inhibitory Activity Against LPS-Induced Inflammation

2021 ◽  
Vol 11 ◽  
Author(s):  
Lulu Zhang ◽  
Xubiao Wei ◽  
Rijun Zhang ◽  
Matthew Koci ◽  
Dayong Si ◽  
...  
Keyword(s):  
Cellular Uptake ◽  
Cell Uptake ◽  
Inflammatory Activity ◽  
Myeloid Differentiation ◽  
Toll Like Receptor 4 ◽  
Native Peptides ◽  
Anti Inflammatory ◽  
Myeloid Differentiation Factor ◽  
Inflammatory Effect ◽  
Lps Binding

Lipopolysaccharide (LPS) has been implicated as a major cause of inflammation and an uncontrolled LPS response increases the risk of localized inflammation and sepsis. While some native peptides are helpful in the treatment of LPS-induced inflammation, the use of these peptides is limited due to their potential cytotoxicity and poor anti-inflammatory activity. Hybridization is an effective approach for overcoming this problem. In this study, a novel hybrid anti-inflammatory peptide that combines the active center of Cathelicidin 2 (CATH2) with thymopentin (TP5) was designed [CTP, CATH2 (1–13)-TP5]. CTP was found to have higher anti-inflammatory effects than its parental peptides through directly LPS neutralization. However, CTP scarcely inhibited the attachment of LPS to cell membranes or suppressed an established LPS-induced inflammation due to poor cellular uptake. The C-terminal amine modification of CTP (CTP-NH2) was then designed based on the hypothesis that C-terminal amidation can enhance the cell uptake by increasing the hydrophobicity of the peptide. Compared with CTP, CTP-NH2 showed enhanced anti-inflammatory activity and lower cytotoxicity. CTP-NH2 not only has strong LPS neutralizing activity, but also can significantly inhibit the LPS attachment and the intracellular inflammatory response. The intracellular anti-inflammatory effect of CTP-NH2 was associated with blocking of LPS binding to the Toll-like receptor 4-myeloid differentiation factor 2 complex and inhibiting the nuclear factor-kappa B pathway. In addition, the anti-inflammatory effect of CTP-NH2 was confirmed using a murine LPS-induced sepsis model. Collectively, these findings suggest that CTP-NH2 could be developed into a novel anti-inflammatory drug. This successful modification provides a design strategy to improve the cellular uptake and anti-inflammatory activity of peptide agents.

scholarly journals Nfa34810 Facilitates Nocardia farcinica Invasion of Host Cells and Stimulates Tumor Necrosis Factor Alpha Secretion through Activation of the NF-κB and Mitogen-Activated Protein Kinase Pathways via Toll-Like Receptor 4

2020 ◽  
Vol 88 (4) ◽  
Author(s):  
Xingzhao Ji ◽  
Xiujuan Zhang ◽  
Heqiao Li ◽  
Lina Sun ◽  
Xuexin Hou ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Host Cells ◽  
Mitogen Activated Protein Kinase ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT The mechanism underlying the pathogenesis of Nocardia is not fully known. The Nfa34810 protein of Nocardia farcinica has been predicted to be a virulence factor. However, relatively little is known regarding the interaction of Nfa34810 with host cells, specifically invasion and innate immune activation. In this study, we aimed to determine the role of recombinant Nfa34810 during infection. We demonstrated that Nfa34810 is an immunodominant protein located in the cell wall. Nfa34810 protein was able to facilitate the uptake and internalization of latex beads coated with Nfa34810 protein into HeLa cells. Furthermore, the deletion of the nfa34810 gene in N. farcinica attenuated the ability of the bacteria to infect both HeLa and A549 cells. Moreover, stimulation with Nfa34810 triggered macrophages to produce tumor necrosis factor alpha (TNF-α), and it also activated mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways by inducing the phosphorylation of ERK1/2, p38, JNK, p65, and AKT in macrophages. Specific inhibitors of ERK1/2, JNK, and NF-κB significantly reduced the expression of TNF-α, which demonstrated that Nfa34810-mediated TNF-α production was dependent upon the activation of these kinases. We further found that neutralizing antibodies against Toll-like receptor 4 (TLR4) significantly inhibited TNF-α secretion. Taken together, our results indicated that Nfa34810 is a virulence factor of N. farcinica and plays an important role during infection. Nfa34810-induced production of TNF-α in macrophages also involves ERK, JNK, and NF-κB via the TLR4 pathway.

scholarly journals Obesity and COVID-19: immune and metabolic derangement as a possible link to adverse clinical outcomes

2020 ◽  
Vol 319 (1) ◽  
pp. E105-E109 ◽  
Author(s):  
Emmanouil Korakas ◽  
Ignatios Ikonomidis ◽  
Foteini Kousathana ◽  
Konstantinos Balampanis ◽  
Aikaterini Kountouri ◽  
...  
Keyword(s):  
Strong Association ◽  
Host Cells ◽  
Low Grade ◽  
Metabolic Derangement ◽  
Innate And Adaptive Immunity ◽  
Monocyte Chemoattractant ◽  
Pyrin Domain ◽  
And Function ◽  
Low Grade Inflammation ◽  
Receptor Family

Recent reports have shown a strong association between obesity and the severity of COVID-19 infection, even in the absence of other comorbidities. After infecting the host cells, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause a hyperinflammatory reaction through the excessive release of cytokines, a condition known as “cytokine storm,” while inducing lymphopenia and a disrupted immune response. Obesity is associated with chronic low-grade inflammation and immune dysregulation, but the exact mechanisms through which it exacerbates COVID-19 infection are not fully clarified. The production of increased amounts of cytokines such as TNFα, IL-1, IL-6, and monocyte chemoattractant protein (MCP-1) lead to oxidative stress and defective function of innate and adaptive immunity, whereas the activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome seems to play a crucial role in the pathogenesis of the infection. Endothelial dysfunction and arterial stiffness could favor the recently discovered infection of the endothelium by SARS-CoV-2, whereas alterations in cardiac structure and function and the prothrombotic microenvironment in obesity could provide a link for the increased cardiovascular events in these patients. The successful use of anti-inflammatory agents such as IL-1 and IL-6 blockers in similar hyperinflammatory settings, like that of rheumatoid arthritis, has triggered the discussion of whether such agents could be administrated in selected patients with COVID-19 disease.

scholarly journals Mast Cell Cytonemes as a Defense Mechanism againstCoxiella burnetii

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Soraya Mezouar ◽  
Joana Vitte ◽  
Laurent Gorvel ◽  
Amira Ben Amara ◽  
Benoit Desnues ◽  
...  
Keyword(s):  
Mast Cells ◽  
Coxiella Burnetii ◽  
Actin Filaments ◽  
Defense Mechanism ◽  
Host Cells ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Content Type ◽  
Microbicidal Activity ◽  
Mediators Of Inflammation

ABSTRACTMast cells (MCs) are critical mediators of inflammation; however, their microbicidal activity against invading pathogens remains largely unknown. Here, we describe a nonpreviously reported antibacterial mechanism used by MCs againstCoxiella burnetii, the agent of Q fever. We show thatC. burnetiiinteraction with MCs does not result in bacterial uptake but rather induces the formation of extracellular actin filaments named cytonemes. MC cytonemes express cathelicidin and neutrophil elastase and mediate the capture and destruction of entrapped bacteria. We provide evidence that MC cytoneme formation and microbicidal activity are dependent on the cooperation of the scavenger receptor CD36 and Toll-like receptor 4. Taken together, our results suggest that MCs use an extracellular sophisticated mechanism of defense to eliminate intracellular pathogens, such asC. burnetii, before their entry into host cells.IMPORTANCEMast cells (MCs) are found in tissues that are in close contact with external environment, such as skin, lungs, or intestinal mucosa but also in the placenta during pregnancy. If their role in mediating allergic conditions is established, several studies now highlight their importance during infection with extracellular pathogens. This study showed a new and effective antimicrobial mechanism of MCs againstCoxiella burnetii, an intracellular bacterium whose infection during pregnancy is associated with abortion, preterm labor, and stillbirth. The data reveal that in response toC. burnetii, MCs release extracellular actin filaments that contain antimicrobial agents and are capable to trap and kill bacteria. We show that this mechanism is dependent on the cooperation of two membrane receptors, CD36 and Toll-like receptor 4, and may occur in the placenta during pregnancy by usingex vivoplacental MCs. Overall, this study reports an unexpected role for MCs during infection with intracellular bacteria and suggests that MC response toC. burnetiiinfection is a protective defense mechanism during pregnancy.

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