scholarly journals Sulfatides are endogenous ligands for the TLR4–MD-2 complex

2021 ◽  
Vol 118 (30) ◽  
pp. e2105316118
Author(s):  
Lijing Su ◽  
Muhammad Athamna ◽  
Ying Wang ◽  
Junmei Wang ◽  
Marina Freudenberg ◽  
...  
Keyword(s):  
Lipid A ◽  
Inflammatory Responses ◽  
Receptor Activation ◽  
Sterile Inflammation ◽  
Human Macrophage ◽  
Type I ◽  
Endogenous Ligands ◽  
Limited Length ◽  
Factor Α ◽  
Myeloid Differentiation Factor

Many endogenous molecules, mostly proteins, purportedly activate the Toll-like receptor 4 (TLR4)–myeloid differentiation factor-2 (MD-2) complex, the innate immune receptor for lipopolysaccharide (LPS) derived from gram-negative bacteria. However, there is no structural evidence supporting direct TLR4–MD-2 activation by endogenous ligands. Sulfatides (3-O-sulfogalactosylceramides) are natural, abundant sulfated glycolipids that have variously been shown to initiate or suppress inflammatory responses. We show here that short fatty acid (FA) chain sulfatides directly activate mouse TLR4–MD-2 independent of CD14, trigger MyD88- and TRIF-dependent signaling, and stimulate tumor necrosis factor α (TNFα) and type I interferon (IFN) production in mouse macrophages. In contrast to the agonist activity toward the mouse receptor, the tested sulfatides antagonize TLR4–MD-2 activation by LPS in human macrophage-like cells. The agonistic and antagonistic activities of sulfatides require the presence of the sulfate group and are inversely related to the FA chain length. The crystal structure of mouse TLR4–MD-2 in complex with C16-sulfatide revealed that three C16-sulfatide molecules bound to the MD-2 hydrophobic pocket and induced an active dimer conformation of the receptor complex similar to that induced by LPS or lipid A. The three C16-sulfatide molecules partially mimicked the detailed interactions of lipid A to achieve receptor activation. Our results suggest that sulfatides may mediate sterile inflammation or suppress LPS-stimulated inflammation, and that additional endogenous negatively charged lipids with up to six lipid chains of limited length might also bind to TLR4–MD-2 and activate or inhibit this complex.

Poly-L-Lysine Induces Fibrosis on Alginate Microcapsules via the Induction of Cytokines

2001 ◽  
Vol 10 (3) ◽  
pp. 263-275 ◽  
Author(s):  
Berit L. Strand ◽  
Liv Ryan ◽  
Peter In't Veld ◽  
Bård Kulseng ◽  
Anne Mari Rokstad ◽  
...  
Keyword(s):  
Lipid A ◽  
Kinase Inhibitor ◽  
Inflammatory Responses ◽  
Type I Diabetes ◽  
Annexin V ◽  
Cell Types ◽  
P38 Map Kinase ◽  
Common Element ◽  
Type I ◽  
Inflammatory Reactions

Alginate – poly-l-lysine (PLL) microcapsules can be used for transplantation of insulin-producing cells for treatment of type I diabetes. In this work we wanted to study the inflammatory reactions against implanted microcapsules due to PLL. We have seen that by reducing the PLL layer, less overgrowth of the capsule is obtained. By incubating different cell types with PLL and afterwards measuring cell viability with MTT, we found massive cell death at concentrations of PLL higher than 10 μg/ml. Staining with annexin V and propidium iodide showed that PLL induced necrosis but not apoptosis. The proinflammatory cytokine, tumor necrosis factor (TNF), was detected in supernatants from monocytes stimulated with PLL. The TNF response was partly inhibited with antibodies against CD14, which is a well-known receptor for lipopolysaccharide (LPS). Bactericidal permeability increasing protein (BPI) and a lipid A analogue (B-975), which both inhibit LPS, did not inhibit PLL from stimulating monocytes to TNF production. This indicates that PLL and LPS bind to different sites on monocytes, but because they both are inhibited by a p38 MAP kinase inhibitor, they seem to have a common element in the signal transducing pathway. These results suggest that PLL may provoke inflammatory responses either directly or indirectly through its necrosis-inducing abilities. By combining soluble PLL and alginate both the toxic and TNF-inducing effects of PLL were reduced. The implications of these data are to use alginate microcapsules with low amounts of PLL for transplantation purposes.

scholarly journals Danger-Associated Molecular Patterns (DAMPs): Molecular Triggers for Sterile Inflammation in the Liver

2018 ◽  
Vol 19 (10) ◽  
pp. 3104 ◽  
Author(s):  
Sabine Mihm
Keyword(s):  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Sterile Inflammation ◽  
Type I Interferons ◽  
Neutrophil Granulocytes ◽  
Type I ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion ◽  
Molecular Patterns

Inflammatory liver diseases in the absence of pathogens such as intoxication by xenobiotics, cholestatic liver injury, hepatic ischemia-reperfusion injury (I/R), non-alcoholic steatohepatitis (NASH), or alcoholic liver disease (ALD) remain threatening conditions demanding specific therapeutic options. Caused by various different noxae, all these conditions have been recognized to be triggered by danger- or death-associated molecular patterns (DAMPs), discompartmentalized self-structures released by dying cells. These endogenous, ectopic molecules comprise proteins, nucleic acids, adenosine triphosphate (ATP), or mitochondrial compounds, among others. This review resumes the respective modes of their release—passively by necrotic hepatocytes or actively by viable or apoptotic parenchymal cells—and their particular roles in sterile liver pathology. It addresses their sensors and the initial inflammatory responses they provoke. It further addresses a resulting second wave of parenchymal death that might be of different mode, boosting the release of additional, second-line DAMPs. Thus, triggering a more complex and pronounced response. Initial and secondary inflammatory responses comprise the activation of Kupffer cells (KCs), the attraction and activation of monocytes and neutrophil granulocytes, and the induction of type I interferons (IFNs) and their effectors. A thorough understanding of pathophysiology is a prerequisite for identifying rational therapeutic targets.

scholarly journals Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

Science ◽  
2020 ◽  
Vol 369 (6504) ◽  
pp. 718-724 ◽  
Author(s):  
Jérôme Hadjadj ◽  
Nader Yatim ◽  
Laura Barnabei ◽  
Aurélien Corneau ◽  
Jeremy Boussier ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Type I ◽  
Therapeutic Approaches ◽  
Host Immune Responses ◽  
Interferon Activity ◽  
Critical Patients ◽  
Factor Α ◽  
Necrosis Factor ◽  
Blood Viral Load

Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression that suggest diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A distinct phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-β and low IFN-α production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor nuclear factor–κB and characterized by increased tumor necrosis factor–α and interleukin-6 production and signaling. These data suggest that type I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.

scholarly journals All-Trans Retinoic Acid Enhances both the Signaling for Priming and the Glycolysis for Activation of NLRP3 Inflammasome in Human Macrophage

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1591
Author(s):  
Ahmad Alatshan ◽  
Gergő E. Kovács ◽  
Azzam Aladdin ◽  
Zsolt Czimmerer ◽  
Krisztina Tar ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Retinoic Acid ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Retinoic Acid Receptor ◽  
Human Monocyte ◽  
Sterile Inflammation ◽  
Human Macrophage ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

All-trans retinoic acid (ATRA) is a derivative of vitamin A that has many important biological functions, including the modulation of immune responses. ATRA actions are mediated through the retinoic acid receptor that functions as a nuclear receptor, either regulating gene transcription in the nucleus or modulating signal transduction in the cytoplasm. NLRP3 inflammasome is a multiprotein complex that is activated by a huge variety of stimuli, including pathogen- or danger-related molecules. Activation of the inflammasome is required for the production of IL-1β, which drives the inflammatory responses of infectious or non-infectious sterile inflammation. Here, we showed that ATRA prolongs the expression of IL-6 and IL-1β following a 2-, 6-, 12-, and 24-h LPS (100ng/mL) activation in human monocyte-derived macrophages. We describe for the first time that ATRA modulates both priming and activation signals required for NLRP3 inflammasome function. ATRA alone induces NLRP3 expression, and enhances LPS-induced expression of NLRP3 and pro-IL-1β via the regulation of signal transduction pathways, like NF-κB, p38, and ERK. We show that ATRA alleviates the negative feedback loop effect of IL-10 anti-inflammatory cytokine on NLRP3 inflammasome function by inhibiting the Akt-mTOR-STAT3 signaling axis. We also provide evidence that ATRA enhances hexokinase 2 expression, and shifts the metabolism of LPS-activated macrophages toward glycolysis, leading to the activation of NLRP3 inflammasome.

scholarly journals TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS

2016 ◽  
Vol 113 (7) ◽  
pp. E884-E893 ◽  
Author(s):  
Ying Wang ◽  
Lijing Su ◽  
Matthew D. Morin ◽  
Brian T. Jones ◽  
Landon R. Whitby ◽  
...  
Keyword(s):  
Lipid A ◽  
Interleukin 1 ◽  
Structural Similarity ◽  
Receptor Activation ◽  
Primary Response ◽  
Myeloid Differentiation ◽  
Toll Like Receptor ◽  
Primary Response Gene ◽  
Tlr4 Ligand ◽  
Myeloid Differentiation Factor

Structurally disparate molecules reportedly engage and activate Toll-like receptor (TLR) 4 and other TLRs, yet the interactions that mediate binding and activation by dissimilar ligands remain unknown. We describe Neoseptins, chemically synthesized peptidomimetics that bear no structural similarity to the established TLR4 ligand, lipopolysaccharide (LPS), but productively engage the mouse TLR4 (mTLR4)/myeloid differentiation factor 2 (MD-2) complex. Neoseptin-3 activates mTLR4/MD-2 independently of CD14 and triggers canonical myeloid differentiation primary response gene 88 (MyD88)- and Toll-interleukin 1 receptor (TIR) domain-containing adaptor inducing IFN-beta (TRIF)-dependent signaling. The crystal structure mTLR4/MD-2/Neoseptin-3 at 2.57-Å resolution reveals that Neoseptin-3 binds as an asymmetrical dimer within the hydrophobic pocket of MD-2, inducing an active receptor complex similar to that induced by lipid A. However, Neoseptin-3 and lipid A form dissimilar molecular contacts to achieve receptor activation; hence strong TLR4/MD-2 agonists need not mimic LPS.

scholarly journals Manipulation of Quercetin and Melatonin in the Down-Regulation of HIF-1α, HSP-70 and VEGF Pathways in Rat’s Kidneys Induced by Hypoxic Stress

Dose-Response ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 155932582094979
Author(s):  
Aliah R. Alshanwani ◽  
Sameerah Shaheen ◽  
Laila M. Faddah ◽  
Ahlam M. Alhusaini ◽  
Hanaa M. Ali ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Histopathological Examination ◽  
Hemoglobin Concentration ◽  
Vascular Endothelial ◽  
Hsp 70 ◽  
Reactive Protein ◽  
Defensive Role ◽  
Factor Α ◽  
Endothelial Growth Factor

Hypoxia may lead to inflammatory responses by numerous signaling pathways. This investigation intended to inspect the defensive role of Quercetin (Quer) and/ or Melatonin (Mel) against reno toxicity induced by Sodium nitrite (Sod ntr). Sod ntr injection significantly decreased blood hemoglobin concentration (Hb) with a concurrent increase in serum tumor necrosis factor- α, interleukin-6, C-reactive protein, creatinine, and urea levels. Over protein-expression of vascular endothelial growth factor and heat shock, protein-70 and mRNA of HIF-1α were also observed. Pretreatment of the Sod ntr- injected rats with the aforementioned antioxidants; either alone or together significantly improved such parameters. Histopathological examination reinforced the previous results. It was concluded that the combined administration of Quer and Mel may be useful as a potential therapy against renal injury induced by Sod ntr. HIF-1α and HSP-70 are implicated in the induction of hypoxia and its treatment.

scholarly journals Early Inflammatory Cytokine Expression in Cerebrospinal Fluid of Patients with Spontaneous Intraventricular Hemorrhage

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1123
Author(s):  
Wendy C. Ziai ◽  
Adrian R. Parry-Jones ◽  
Carol B. Thompson ◽  
Lauren H. Sansing ◽  
Michael T. Mullen ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Intraventricular Hemorrhage ◽  
Inflammatory Responses ◽  
Obstructive Hydrocephalus ◽  
External Ventricular Drainage ◽  
Enzyme Linked Immunosorbent Assay ◽  
Injury Reduction ◽  
Positive Correlations ◽  
Factor Α ◽  
Perihematomal Edema

We investigated cerebrospinal fluid (CSF) expression of inflammatory cytokines and their relationship with spontaneous intracerebral and intraventricular hemorrhage (ICH, IVH) and perihematomal edema (PHE) volumes in patients with acute IVH. Twenty-eight adults with IVH requiring external ventricular drainage for obstructive hydrocephalus had cerebrospinal fluid (CSF) collected for up to 10 days and had levels of interleukin-1α (IL-1α), IL-1β, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNFα), and C-C motif chemokine ligand CCL2 measured using enzyme-linked immunosorbent assay. Median [IQR] ICH and IVH volumes at baseline (T0) were 19.8 [5.8–48.8] and 14.3 [5.3–38] mL respectively. Mean levels of IL-1β, IL-6, IL-10, TNF-α, and CCL2 peaked early compared to day 9–10 (p < 0.05) and decreased across subsequent time periods. Levels of IL-1β, IL-6, IL-8, IL-10, and CCL2 had positive correlations with IVH volume at days 3–8 whereas positive correlations with ICH volume occurred earlier at day 1–2. Significant correlations were found with PHE volume for IL-6, IL-10 and CCL2 at day 1–2 and with relative PHE at days 7–8 or 9–10 for IL-1β, IL-6, IL-8, and IL-10. Time trends of CSF cytokines support experimental data suggesting association of cerebral inflammatory responses with ICH/IVH severity. Pro-inflammatory markers are potential targets for injury reduction.

scholarly journals H2-antagonist in IgE-mediated type I hypersensitivity reactions: what literature says so far?

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Matteo Borro ◽  
Simone Negrini ◽  
Andrew Long ◽  
Sharon Chinthrajah ◽  
Giuseppe Murdaca
Keyword(s):  
Receptor Antagonist ◽  
Inflammatory Responses ◽  
Type I ◽  
Line Therapy ◽  
H2 Antagonist ◽  
Amino Acid Histidine ◽  
Third Line Therapy ◽  
Ige Mediated ◽  
Third Line ◽  
Type I Hypersensitivity

AbstractHistamine is a monoamine synthesized from the amino acid histidine that is well-known for its role in IgE-mediated anaphylaxis but has shown pleiotropic effects on the immune system, especially in order to promote inflammatory responses. H1-receptor antagonist are common drugs used in mild/moderate allergic reactions whereas H2-receptor antagonist are commonly administered in gastric ulcer but showed some properties in allergy too. The EAACI guidelines for diagnosis and treatment of anaphylactic reactions recommend their use as third-line therapy in adjunct to H1-antagonists. The purpose of this article is to produce a complete summary of findings and evidence known so far about the usefulness of H2-receptor antagonist in allergic reactons.

scholarly journals Growth Arrest-Specific Factor 6 (GAS6) Is Increased in COVID-19 Patients and Predicts Clinical Outcome

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 335
Author(s):  
Albert Morales ◽  
Silvia Rojo Rello ◽  
Helena Cristóbal ◽  
Aida Fiz-López ◽  
Elisa Arribas ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Growth Arrest ◽  
Emergency Admission ◽  
Human Macrophage ◽  
Specific Factor ◽  
Alveolar Cells ◽  
Lps Challenge ◽  
Tam Receptors ◽  
Relevant Role ◽  
Severity Of The Disease

Background: Growth arrest-specific factor 6 (GAS6) and the Tyro3, AXL, and MERTK (TAM) receptors counterbalance pro-inflammatory responses. AXL is a candidate receptor for SARS-CoV-2, particularly in the respiratory system, and the GAS6/AXL axis is targeted in current clinical trials against COVID-19. However, GAS6 and TAMs have not been evaluated in COVID-19 patients at emergency admission. Methods: Plasma GAS6, AXL, and MERTK were analyzed in 132 patients consecutively admitted to the emergency ward during the first peak of COVID-19. Results: GAS6 levels were higher in the SARS-CoV-2-positive patients, increasing progressively with the severity of the disease. Patients with initial GAS6 at the highest quartile had the worst outcome, with a 3-month survival of 65%, compared to a 90% survival for the rest. Soluble AXL exhibited higher plasma concentration in deceased patients, without significant differences in MERTK among SARS-CoV-2-positive groups. GAS6 mRNA was mainly expressed in alveolar cells and AXL in airway macrophages. Remarkably, THP-1 human macrophage differentiation neatly induces AXL, and its inhibition (bemcentinib) reduced cytokine production in human macrophages after LPS challenge. Conclusions: Plasma GAS6 and AXL levels reflect COVID-19 severity and could be early markers of disease prognosis, supporting a relevant role of the GAS6/AXL system in the immune response in COVID-19.

scholarly journals CD36 deficiency ameliorates drug-induced acute liver injury in mice

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Chen Zhang ◽  
Xiao Shi ◽  
Zhongping Su ◽  
Chao Hu ◽  
Xianmin Mu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Western Blot ◽  
Kinase Inhibitor ◽  
Inflammatory Responses ◽  
Acute Liver Injury ◽  
Protein Adducts ◽  
Sterile Inflammation ◽  
Inflammatory Factor ◽  
Cd36 Deficiency ◽  
Significant Difference

Abstract Background Acetaminophen (APAP) overdose causes hepatotoxicity and even acute liver failure. Recent studies indicate that sterile inflammation and innate immune cells may play important roles in damage-induced hepatocytes regeneration and liver repair. The scavenger receptor CD36 has its crucial functions in sterile inflammation. However, the roles of CD36 in APAP induced acute liver injury remain unclear and warrant further investigation. Methods WT C57BL/6 J and CD36−/− mice were intraperitoneally injected with APAP (300 mg/kg) after fasting for 16 h. Liver injury was evaluated by serum alanine aminotransferase (ALT) level and liver tissue hematoxylin and eosin (H&E) staining. Liver inflammatory factor expression was determined by real-time polymerase chain reaction (PCR). The protein adducts forming from the metabolite of APAP and the metabolism enzyme cytochrome P450 2E1 (CYP2E1) levels were measured by Western blot. Liver infiltrating macrophages and neutrophils were characterized by flow cytometry. RNA sequencing and Western blot were used to evaluate the effect of damage-associated molecular patterns (DAMP) molecule high mobility group B1 (HMGB1) on WT and CD36−/− macrophages. Moreover, PP2, a Src kinase inhibitor, blocking CD36 signaling, was applied in APAP model. Results The expression of CD36 was increased in the liver of mice after APAP treatment. Compared with WT mice, APAP treated CD36−/− mice show less liver injury. There was no significant difference in APAP protein adducts and CYP2E1 expression between these two strains. However, reduced pro-inflammatory factor mRNA expression and serum IL-1β level were observed in APAP treated CD36−/− mice as well as infiltrating macrophages and neutrophils. Moreover, CD36 deficiency impaired the activation of c-Jun N-terminal kinase (JNK) caused by APAP. Interestingly, the lack of CD36 reduced the activation of extracellular regulated protein kinases (Erk) and v-akt murine thymoma viral oncogene homolog (Akt) induced by HMGB1. RNA transcription sequencing data indicated that HMGB1 has a different effect on WT and CD36−/− macrophages. Furthermore, treatment with PP2 attenuated APAP induced mouse liver injury. Conclusion Our data demonstrated that CD36 deficiency ameliorated APAP-induced acute liver injury and inflammatory responses by decreasing JNK activation. CD36 might serve as a new target to reduce acute liver injury.

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