Natural Sulfurs Inhibit LPS-Induced Inflammatory Responses through NF-κB Signaling in CCD-986Sk Skin Fibroblasts

Lipopolysaccharide (LPS)-induced inflammatory response leads to serious damage, up to and including tumorigenesis. Natural mineral sulfur, non-toxic sulfur (NTS), and methylsulfonylmethane (MSM) have anti-inflammatory activity that may inhibit LPS-induced inflammation. We hypothesized that sulfur compounds could inhibit LPS-induced inflammatory responses in CCD-986Sk skin fibroblasts. We used Western blotting and real-time PCR to analyze molecular signaling in treated and untreated cultures. We also used flow cytometry for cell surface receptor analysis, comet assays to evaluate DNA damage, and ELISA-based cytokine detection. LPS induced TLR4 activation and NF-κB signaling via canonical and protein kinase C (PKC)-dependent pathways, while NTS and MSM downregulated that response. NTS and MSM also inhibited LPS-induced nuclear accumulation and binding of NF-κB to proinflammatory cytokines COX-2, IL-1β, and IL-6. Finally, the sulfur compounds suppressed LPS-induced ROS accumulation and DNA damage in CCD-986Sk cells. These results suggest that natural sulfur compounds could be used to treat inflammation and may be useful in the development of cosmetics.

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The Role of Hyaluronan and CD44 in the Pathogenesis of Lupus Nephritis

Autoimmune Diseases ◽

10.1155/2012/207190 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 7

Author(s):

Susan Yung ◽

Tak Mao Chan

Keyword(s):

Lupus Nephritis ◽

Lupus Erythematosus ◽

Inflammatory Responses ◽

Tissue Injury ◽

Cell Surface Receptor ◽

Systemic Lupus ◽

Permanent Damage ◽

Immune Mediated ◽

Surface Receptor

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that affects multiorgan systems. Lupus nephritis is one of the most severe manifestations of SLE whereby immune-mediated inflammation can lead to permanent damage within the glomerular, tubulo-interstitial, and vascular compartments of the kidney, resulting in acute or chronic renal failure. The mechanisms that regulate host inflammatory responses and tissue injury are incompletely understood. Accumulating evidence suggests that hyaluronan and its interaction with its cell surface receptor CD44 plays an important role in mediating pathogenic mechanisms in SLE. This paper discusses the putative mechanisms through which hyaluronan and CD44 contribute to the pathogenesis of SLE, with particular emphasis on lupus nephritis.

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LRP1 integrates murine macrophage cholesterol homeostasis and inflammatory responses in atherosclerosis

eLife ◽

10.7554/elife.29292 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 25

Author(s):

Xunde Xian ◽

Yinyuan Ding ◽

Marco Dieckmann ◽

Li Zhou ◽

Florian Plattner ◽

...

Keyword(s):

Inflammatory Responses ◽

Apoptotic Cell ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Vascular Wall ◽

Cholesterol Homeostasis ◽

Cell Surface Receptor ◽

Wide Range ◽

Surface Receptor

Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional cell surface receptor with diverse physiological roles, ranging from cellular uptake of lipoproteins and other cargo by endocytosis to sensor of the extracellular environment and integrator of a wide range of signaling mechanisms. As a chylomicron remnant receptor, LRP1 controls systemic lipid metabolism in concert with the LDL receptor in the liver, whereas in smooth muscle cells (SMC) LRP1 functions as a co-receptor for TGFβ and PDGFRβ in reverse cholesterol transport and the maintenance of vascular wall integrity. Here we used a knockin mouse model to uncover a novel atheroprotective role for LRP1 in macrophages where tyrosine phosphorylation of an NPxY motif in its intracellular domain initiates a signaling cascade along an LRP1/SHC1/PI3K/AKT/PPARγ/LXR axis to regulate and integrate cellular cholesterol homeostasis through the expression of the major cholesterol exporter ABCA1 with apoptotic cell removal and inflammatory responses.

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Sustained TREM2 stabilization accelerates microglia heterogeneity and Abeta pathology in a mouse model of Alzheimer s disease

10.1101/2021.06.23.449405 ◽

2021 ◽

Author(s):

Rahul Dhandapani ◽

Marilisa Neri ◽

Mario Bernhard ◽

Irena Brzak ◽

Tatjana Schweizer ◽

...

Keyword(s):

Mouse Model ◽

Inflammatory Responses ◽

Transmembrane Protein ◽

Proteolytic Cleavage ◽

Cell Surface Receptor ◽

Pathological Conditions ◽

Mouse Cortex ◽

Surface Receptor ◽

And Function ◽

The Brain

TREM2 is a transmembrane protein expressed exclusively in microglia in the brain that regulates inflammatory responses to pathological conditions. Proteolytic cleavage of membrane TREM2 affects microglial function and is associated with Alzheimer s disease, but the consequence of reduced TREM2 proteolytic cleavage has not been determined. We generated a transgenic mouse model of reduced TREM2 shedding (Trem2-IPD) through amino acid substitution of ADAM-protease recognition site. We found that Trem2-IPD mice displayed increased TREM2 cell surface receptor load, survival and function in myeloid cells. Using single cell transcriptomic profiling of mouse cortex we show that sustained TREM2 stabilization induces a shift of fate in microglial maturation and accelerates microglial responses to Abeta pathology in a mouse model of Alzheimer s disease. Our data indicate that reduction of TREM2 proteolytic cleavage aggravates neuroinflammation during the course of AD pathology suggesting that TREM2 shedding is a critical regulator of microglial activity in pathological states.

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Soluble TREM2 induces inflammatory responses and enhances microglial survival

Journal of Experimental Medicine ◽

10.1084/jem.20160844 ◽

2017 ◽

Vol 214 (3) ◽

pp. 597-607 ◽

Cited By ~ 100

Author(s):

Li Zhong ◽

Xiao-Fen Chen ◽

Tingting Wang ◽

Zhe Wang ◽

Chunyan Liao ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Morphological Changes ◽

Cell Surface Receptor ◽

Soluble Form ◽

Dependent Manner ◽

Soluble Trem2 ◽

Surface Receptor ◽

The Brain ◽

Ad Therapy

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed in microglia in the brain. A soluble form of TREM2 (sTREM2) derived from proteolytic cleavage of the cell surface receptor is increased in the preclinical stages of AD and positively correlates with the amounts of total and phosphorylated tau in the cerebrospinal fluid. However, the physiological and pathological functions of sTREM2 remain unknown. Here, we show that sTREM2 promotes microglial survival in a PI3K/Akt-dependent manner and stimulates the production of inflammatory cytokines depending on NF-κB. Variants of sTREM2 carrying AD risk-associated mutations were less potent in both suppressing apoptosis and triggering inflammatory responses. Importantly, sTREM2 delivered to the hippocampi of both wild-type and Trem2-knockout mice elevated the expression of inflammatory cytokines and induced morphological changes of microglia. Collectively, these data indicate that sTREM2 triggers microglial activation inducing inflammatory responses and promoting survival. This study has implications for the pathogenesis of AD and provides insights into targeting sTREM2 pathway for AD therapy.

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Immunomodulatory Glycan Lacto-N-Fucopentaose III Requires Clathrin-Mediated Endocytosis To Induce Alternative Activation of Antigen-Presenting Cells

Infection and Immunity ◽

10.1128/iai.01293-13 ◽

2014 ◽

Vol 82 (5) ◽

pp. 1891-1903 ◽

Cited By ~ 15

Author(s):

Leena Srivastava ◽

Smanla Tundup ◽

Beak-San Choi ◽

Thomas Norberg ◽

Donald Harn

Keyword(s):

Inflammatory Responses ◽

Antigen Presenting Cells ◽

Endocytic Pathway ◽

Cell Surface Receptor ◽

Alternative Activation ◽

Organ Rejection ◽

Surface Receptor ◽

Anti Inflammatory ◽

Antigen Presenting

ABSTRACTThe mechanism of alternative activation of antigen-presenting cells (APCs) is largely unknown. Lacto-N-fucopentaose III (LNFPIII) is a biologically conserved pentasaccharide that contains the Lewisxtrisaccharide. LNFPIII conjugates and schistosome egg antigens, which contain the Lewisxtrisaccharide, drive alternative activation of APCs and induce anti-inflammatory responsesin vivo, preventing inflammation-based diseases, including psoriasis, transplant organ rejection, and metabolic disease. In this study, we show that LNFPIII conjugates and schistosome egg antigens interact with APCs via a receptor-mediated process, requiring internalization of these molecules through a clathrin/dynamin-dependent but caveolus-independent endocytic pathway. Using inhibitors/small interfering RNA (siRNA) against dynamin and clathrin, we show for the first time that endocytosis of Lewisx-containing glycans is required to drive alternative maturation of antigen-presenting cells and Th2 immune responses. We identified mouse SIGNR-1 as a cell surface receptor for LNFPIII conjugates. Elimination of SIGNR-1 showed no effect on uptake of LNFPIII conjugates, suggesting that other receptors bind to and facilitate uptake of LNFPIII conjugates. We demonstrate that disruption of actin filaments partially prevented the entry of LNFPIII conjugates into APCs and that LNFPIII colocalizes with both early and late endosomal markers and follows the classical endosomal pathway leading to lysosome maturation. The results of this study show that the ability of LNFPIII to induce alternative activation utilizes a receptor-mediated process that requires a dynamin-dependent endocytosis. Thus, key steps have been defined in the previously unknown mechanism of alternative activation that ultimately leads to induction of anti-inflammatory responses.

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Enzyme-Treated Asparagus Extract Prevents Hydrogen Peroxide-Induced Pro-Inflammatory Responses by Suppressing p65 Nuclear Translocation in Skin L929 Fibroblasts

Natural Product Communications ◽

10.1177/1934578x1601101227 ◽

2016 ◽

Vol 11 (12) ◽

pp. 1934578X1601101 ◽

Cited By ~ 1

Author(s):

Ken Shirato ◽

Jun Takanari ◽

Takuya Sakurai ◽

Junetsu Ogasawara ◽

Kazuhiko Imaizumi ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Nuclear Translocation ◽

Inflammatory Responses ◽

Nuclear Factor Κb ◽

Skin Fibroblasts ◽

Nuclear Accumulation ◽

Inos Mrna ◽

Mrna Levels ◽

Aging Effects ◽

L929 Cells

We recently reported that enzyme-treated asparagus extract (ETAS) attenuates hydrogen peroxide (H2O2)-stimulated matrix metalloproteinase-9 expression in skin fibroblast L929 cells. To further elucidate the anti-aging effects of ETAS on skin, we examined whether ETAS has preventive effects on H2O2-induced pro-inflammatory responses of skin fibroblasts. H2O2 induced Ser536 phosphorylation and nuclear accumulation of nuclear factor-κB (NF-κB) p65, and increased the mRNA levels of interleukin-12α (IL-12α) and inducible nitric oxide synthase (iNOS) in L929 cells. Pretreatment of the cells with JSH-23, an inhibitor of NF-κB nuclear translocation, abolished the H2O2-induced expression of IL-12α and iNOS, indicating that the increased transcription is regulated by p65. The H2O2-stimulated nuclear accumulation of p65 and induction of IL-12α and iNOS mRNA were significantly attenuated after pretreatment with ETAS for 3 h, and these responses were completely abolished when the duration was extended to 24 h. However, ETAS did not affect the H2O2-stimulated degradation of IκBα and phosphorylation of p65. On the other hand, ETAS treatment for 24 h resulted in decreased protein levels of importin-α. These results suggest that ETAS prevents pro-inflammatory responses by suppressing the p65 nuclear translocation in skin fibroblasts induced by H2O2.

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Interferon and heparan sulphate

Biochemical Society Transactions ◽

10.1042/bst0340461 ◽

2006 ◽

Vol 34 (3) ◽

pp. 461-464 ◽

Cited By ~ 9

Author(s):

H. Lortat-Jacob

Keyword(s):

Binding Site ◽

Inflammatory Responses ◽

Heparan Sulphate ◽

Cell Surface Receptor ◽

Type I ◽

Structural Determinants ◽

Controlled Processing ◽

Rich Domain ◽

New Strategy ◽

Surface Receptor

In 1954, substances that protected cells from viral infection were discovered and named IFN (interferon). This family of cytokines, which were the first to be used in clinical therapy, is classified into type I and II IFNs. Type I mainly consists of IFNα and IFNβ subtypes, which are structurally related and bind to a common receptor. IFNγ, the sole type II IFN, is structurally unrelated, binds to a different receptor and, as a dimer, strongly interacts with HS (heparan sulphate). In addition to its antiviral activity, it modulates nearly all phases of immune and inflammatory responses. IFNγ binding to HS controls the blood clearance, the subsequent tissue targeting and the local accumulation of the cytokine. It also regulates IFNγ activity by a unique mechanism involving a controlled processing of the C-terminal peptide. The binding site encompasses an N-acetylated glucosamine-rich domain separating two highly sulphated sequences that each binds to one IFNγ monomer. Based on this template, a set of glycoconjugate mimetics that would mimic the IFNγ binding site has been synthesized. One of these molecules displays high affinity for the cytokine and inhibits binding to both HS and IFNγR (IFNγ receptor), the cell-surface receptor. These results validate the HS structural determinants for IFNγ recognition, and provide a new strategy to inhibit IFNγ in a number of diseases in which the cytokine has been identified as a target.

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Maternal-embryonic approach at Covid-19:

Jornal Memorial da Medicina ◽

10.37085/jmmv2.n1.2020.pp.51-59 ◽

2020 ◽

Vol 2 (1) ◽

pp. 51-59

Author(s):

Roberta Simões Guerra ◽

Vanessa Cristina Castro Carvalho ◽

Erlene Roberta Ribeiro dos Santos ◽

Luciano De Albuquerque Mello

Keyword(s):

Pregnant Women ◽

Inflammatory Responses ◽

Risk Groups ◽

Cell Surface Receptor ◽

Angiotensin Converting Enzyme 2 ◽

Face To Face ◽

Peace Of Mind ◽

Surface Receptor ◽

A Cell ◽

Virtual Assistance

The pathophysiology of Covid-19 has a cytokine storm, causing exacerbation of inflammatory lesions, mainly of the lungs and vascular endothelium. The mechanism of entry into the human cell uses the Angiotensin-Converting Enzyme 2 as a cell surface receptor. Among the most at-risk groups are pregnant women, due to the physiological, anatomical and immunological changes of the gestational cycle, causing susceptibility to infections. In addition, there are uncertainties about safe breastfeeding and possible vertical transmission. This group, which has a continuous obstetric follow-up, within pandemic circumstances, needed to minimize the risk of exposure in medical settings, using care through telehealth, as a helper. It was possible to replace some face-to-face visits to the clinic, when possible, by virtual ones, minimizing risks to exposure and providing a vehicle for direct communication with the doctor, which, in a way, offers pregnant women more peace of mind, essential to avoid possible complications by psychological stress that can generate inflammatory responses for mother and fetus, causing possible neuropsychiatric consequences. The objective of this narrative review study was to present an update of the data on the disease, as well as a change in management of the pregnant population. Despite being of great importance, virtual assistance does not replace face-to-face, and to get the most out of this new approach, there is a set of guidelines that can help health professionals. It is also important to warn of: changes in hospital management; reconciling ultrasound consultations with medical appointments, reducing the number of pregnant women leavings; telephone tracking of patients' symptoms before face-to-face attendance; and testing recommendations for covid-19, before entering hospitals.

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