scholarly journals Synergy between 15-lipoxygenase and secreted PLA2promotes inflammation by formation of TLR4 agonists from extracellular vesicles

2020 ◽  
Vol 117 (41) ◽  
pp. 25679-25689 ◽  
Author(s):  
Van Thai Ha ◽  
Duško Lainšček ◽  
Bernd Gesslbauer ◽  
Eva Jarc-Jovičić ◽  
Tuulia Hyötyläinen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune Response ◽  
Extracellular Vesicles ◽  
Acyl Chain ◽  
Innate Immune ◽  
Sterile Inflammation ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Unsaturated Acyl

Damage-associated endogenous molecules induce innate immune response, thus making sterile inflammation medically relevant. Stress-derived extracellular vesicles (stressEVs) released during oxidative stress conditions were previously found to activate Toll-like receptor 4 (TLR4), resulting in expression of a different pattern of immune response proteins in comparison to lipopolysaccharide (LPS), underlying the differences between pathogen-induced and sterile inflammation. Here we report that synergistic activities of 15-lipoxygenase (15-LO) and secreted phospholipase A2(sPLA2) are needed for the formation of TLR4 agonists, which were identified as lysophospholipids (lysoPLs) with oxidized unsaturated acyl chain. Hydroxy, hydroperoxy, and keto products of 2-arachidonoyl-lysoPI oxidation by 15-LO were identified by mass spectrometry (MS), and they activated the same gene pattern as stressEVs. Extracellular PLA2activity was detected in the synovial fluid from rheumatoid arthritis and gout patients. Furthermore, injection of sPLA2promoted K/BxN serum-induced arthritis in mice, whereby ankle swelling was partially TLR4 dependent. Results confirm the role of oxidized lysoPL of stressEVs in sterile inflammation that promotes chronic diseases. Both 15-LO and sPLA2enzymes are induced during inflammation, which opens the opportunity for therapy without compromising innate immunity against pathogens.

scholarly journals Variability among Macaca fascicularis in the innate immune response to Toll‐like receptor 4 (TLR4) agonists

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Charles Wayne Frevert ◽  
Renee Hukkanen ◽  
Steve Mongovin ◽  
Kay Larsen ◽  
Mike Agy ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Macaca Fascicularis ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Monica Molteni ◽  
Sabrina Gemma ◽  
Carlo Rossetti
Keyword(s):  
Tissue Injury ◽  
Sterile Inflammation ◽  
Research Progress ◽  
Toll Like Receptor ◽  
Proinflammatory Response ◽  
Toll Like Receptor 4 ◽  
The Family ◽  
Tlr4 Activation ◽  
Molecular Patterns

Toll-like receptor 4 (TLR4) belongs to the family of pattern recognition receptors (PRRs). They are highly conserved receptors that recognize conserved pathogen-associated molecular patterns (PAMPs), thus representing the first line of defense against infections. TLR4 has been long recognized as the sensing receptor for gram-negative lipopolysaccharide (LPS). In addition, it also binds endogenous molecules produced as a result of tissue injury. Hence, TLR4 represents a key receptor on which both infectious and noninfectious stimuli converge to induce a proinflammatory response. TLR4-mediated inflammation, triggered by exogenous or endogenous ligands, is also involved in several acute and chronic diseases, having a pivotal role as amplifier of the inflammatory response. This review focuses on the research progress about the role of TLR4 activation in infectious and noninfectious (e.g., sterile) inflammation and the effects of TLR4 signaling in some pathological conditions.

Toll-like receptor-4 expressed on gastric pit cells may initiate innate immune response of gastric mucosa against Helicobactor pylori infection

2001 ◽  
Vol 120 (5) ◽  
pp. A59
Author(s):  
Kazuhito Rokutan ◽  
Shigetada Teshima ◽  
Tsukasa Kawahara ◽  
Tomoko Kawai ◽  
Takeshi Nikawa ◽  
...  
Keyword(s):  
Immune Response ◽  
Gastric Mucosa ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Helicobactor Pylori ◽  
Pit Cells

scholarly journals Energetics of Endotoxin Recognition in the Toll-Like Receptor 4 Innate Immune Response

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Teresa Paramo ◽  
Susana M. Tomasio ◽  
Kate L. Irvine ◽  
Clare E. Bryant ◽  
Peter J. Bond
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals Ozone-induced lung injury and sterile inflammation. Role of toll-like receptor 4

2012 ◽  
Vol 92 (2) ◽  
pp. 229-235 ◽  
Author(s):  
Agnieszka J. Connor ◽  
Jeffrey D. Laskin ◽  
Debra L. Laskin
Keyword(s):  
Lung Injury ◽  
Sterile Inflammation ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals Trichinella spiralis: impact on the expression of Toll-like receptor 4 (TLR4) gene during the intestinal phase of experimental trichinellosis

2018 ◽  
Vol 62 (4) ◽  
pp. 493-496
Author(s):  
Agnieszka Wojtkowiak-Giera ◽  
Elżbieta Wandurska-Nowak ◽  
Monika Derda ◽  
Wiesława Jankowska ◽  
Paweł P. Jagodziński ◽  
...  
Keyword(s):  
Immune Response ◽  
Trichinella Spiralis ◽  
Mrna Level ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Intestinal Phase ◽  
Strong Positive Reaction ◽  
Tlr4 Gene ◽  
Rapid Activation

AbstractIntroduction: Toll-like receptors (TLRs) play a key role in the rapid activation of the innate immune response to a variety of pathogens. The aim of this study was to evaluate the effect of Trichinella spiralis infection on the level of expression of the tlr4 gene in mouse intestines during the intestinal phase of experimental trichinellosis.Material and Methods: The experimental material consisted of the small and large intestines of BALB/c mice infected with Trichinella spiralis sampled at 4, 8, and 16 days post infection (dpi).Results: A statistically significant increase was demonstrated in the tlr4 mRNA level isolated from the infected mice jejunum at 4, 8, and 16 dpi over the uninfected control. Moreover, at 4, 8, and 16 dpi in the jejunum of infected mice, a strong positive reaction for the presence of TLR4 protein compared with that of uninfected mice was observed.Conclusion: Infection with T. spiralis changes the expression of the tlr4 gene in the small intestine of the mouse host.

scholarly journals Role ofToll-Like Receptor 4 in Gram-Positive and Gram-Negative Pneumonia inMice

2004 ◽  
Vol 72 (2) ◽  
pp. 788-794 ◽  
Author(s):  
Judith Branger ◽  
Sylvia Knapp ◽  
Sebastiaan Weijer ◽  
Jaklien C. Leemans ◽  
Jennie M. Pater ◽  
...  
Keyword(s):  
Immune Response ◽  
Mutant Mice ◽  
Respiratory Pathogen ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Gram Positive ◽  
Gram Negative ◽  
High Level ◽  
Bacterial Outgrowth

ABSTRACT To determine the role of Toll-like receptor 4 (TLR4) in the immune response to pneumonia, C3H/HeJ mice (which display a mutant nonfunctional TLR4) and C3H/HeN wild-type mice were intranasally infected with either Streptococcus pneumoniae (a common gram-positive respiratory pathogen) or Klebsiella pneumoniae (a common gram-negative respiratory pathogen). In cases of pneumococcal pneumonia, TLR4 mutant mice showed a reduced survival only after infection with low-level bacterial doses, which was associated with a higher bacterial burden in their lungs 48 h postinfection. In Klebsiella pneumonia, TLR4 mutant mice demonstrated a shortened survival after infection with either a low- or a high-level bacterial dose together with an enhanced bacterial outgrowth in their lungs. These data suggest that TLR4 contributes to a protective immune response in both pneumococcal and Klebsiella pneumonia and that its role is more important in respiratory tract infection caused by the latter (gram-negative) pathogen.

scholarly journals Identification of PGN_1123 as the Gene Encoding Lipid A Deacylase, an Enzyme Required for Toll-Like Receptor 4 Evasion, inPorphyromonas gingivalis

2019 ◽  
Vol 201 (11) ◽  
Author(s):  
Sumita Jain ◽  
Ana M. Chang ◽  
Manjot Singh ◽  
Jeffrey S. McLean ◽  
Stephen R. Coats ◽  
...  
Keyword(s):  
Immune Response ◽  
Porphyromonas Gingivalis ◽  
Innate Immune Response ◽  
Lipid A ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Gene Encoding ◽  
Content Type ◽  
Chronic Inflammatory Condition

ABSTRACTRemoval of one acyl chain from bacterial lipid A by deacylase activity is a mechanism used by many pathogenic bacteria to evade the host's Toll-like receptor 4 (TLR4)-mediated innate immune response. InPorphyromonas gingivalis, a periodontal pathogen, lipid A deacylase activity converts a majority of the initially synthesized penta-acylated lipid A, a TLR4 agonist, to tetra-acylated structures, which effectively evade TLR4 sensing by being either inert or antagonistic at TLR4. In this paper, we report successful identification of the gene that encodes theP. gingivalislipid A deacylase enzyme. This gene, PGN_1123 inP. gingivalis33277, is highly conserved withinP. gingivalis, and putative orthologs are phylogenetically restricted to theBacteroidetesphylum. Lipid A of ΔPGN_1123 mutants is penta-acylated and devoid of tetra-acylated structures, and the mutant strain provokes a strong TLR4-mediated proinflammatory response, in contrast to the negligible response elicited by wild-typeP. gingivalis. Heterologous expression of PGN_1123 inBacteroides thetaiotaomicronpromoted lipid A deacylation, confirming that PGN_1123 encodes the lipid A deacylase enzyme.IMPORTANCEPeriodontitis, commonly referred to as gum disease, is a chronic inflammatory condition that affects a large proportion of the population.Porphyromonas gingivalisis a bacterium closely associated with periodontitis, although how and if it is a cause for the disease are not known. It has a formidable capacity to dampen the host's innate immune response, enabling its persistence in diseased sites and triggering microbial dysbiosis in animal models of infection.P. gingivalisis particularly adept at evading the host's TLR4-mediated innate immune response by modifying the structure of lipid A, the TLR4 ligand. In this paper, we report identification of the gene encoding lipid A deacylase, a key enzyme that modifies lipid A to TLR4-evasive structures.

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