scholarly journals 5-HT2Bserotonin receptor agonist BW723C86 shapes the macrophage gene profile via AhR and impairs monocyte-to-osteoclast differentiation

2019 ◽  
Author(s):  
Concha Nieto ◽  
Ignacio Rayo ◽  
Mateo de las Casas-Engel ◽  
Elena Izquierdo ◽  
Bárbara Alonso ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Inflammatory Responses ◽  
Osteoclast Differentiation ◽  
Human Macrophage ◽  
List Type ◽  
Human Macrophages ◽  
Aryl Hydrocarbon ◽  
Anti Inflammatory ◽  
Independent Effects

ABSTRACTPeripheral serotonin (5-HT) exacerbates or limits inflammatory pathologies through interaction with seven types of 5-HT receptors (5-HT1-7). As central regulators of inflammation, macrophages are critical targets of 5-HT, which promotes their anti-inflammatory and pro-fibrotic polarization primarily via the 5-HT7-Protein Kinase A (PKA) axis. However, anti-inflammatory human macrophages are also characterized by the expression of 5-HT2B, an off-target of anesthetics, anti-parkinsonian drugs and Selective Serotonin Reuptake Inhibitors (SSRI) that contributes to 5-HT-mediated pathologies. Since 5-HT2Bprevents mononuclear phagocyte degeneration in amyotrophic lateral sclerosis and modulates motility of murine microglial processes, we sought to determine the functional and transcriptional consequences of 5-HT2Bactivation in human macrophages. Ligation of 5-HT2Bby the 5-HT2B-specific agonist BW723C86, which exhibits antidepressant- and anxiolytic-like effects in animal models, significantly modified the cytokine profile and the transcriptional signature in macrophages. Importantly, 5-HT2Bagonist-induced transcriptional changes were partly mediated through activation of the Aryl hydrocarbon Receptor (AhR), a ligand-dependent transcription factor that regulates immune responses and the biological responses to xenobiotics. Besides, BW723C86 triggered transcriptional effects that could not be abrogated by 5-HT2Bantagonists and impaired monocyte-to-osteoclast differentiation by affecting the expression of negative (IRF8) and positive (PRDM1) regulators of osteoclastogenesis. Therefore, our results demonstrate the existence of a functional 5-HT2B-AhR axis in human macrophages and indicate that the commonly used 5-HT2Bagonist BW723C86 exhibits 5-HT2B-independent effects. The 5-HT2B-AhR link extends the range of signaling pathways initiated upon 5-HT receptor engagement and identifies a point of convergence for endogenous and exogenous agents with ability to modulate inflammatory responses.KEY POINTS-The serotonin receptor 5-HT2Bmodifies the human macrophage transcriptome through activation of the Aryl Hydrocarbon Receptor.-BW723C86, an agonist used for 5-HT2Bactivationin vivo, exerts 5-HT2B-independent effects and limits monocyte osteoclastogenic potential.

Potential role of a series of lysine-/leucine-rich antimicrobial peptide in inhibiting lipopolysaccharide-induced inflammation

2018 ◽  
Vol 475 (22) ◽  
pp. 3687-3706 ◽  
Author(s):  
Weibing Dong ◽  
Xin Zhu ◽  
Xuan Zhou ◽  
Ying Yang ◽  
Xin Yan ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Signaling Pathway ◽  
Inflammatory Responses ◽  
Antimicrobial Activities ◽  
Host Cells ◽  
Inflammatory Factors ◽  
Human Macrophage ◽  
U937 Cells ◽  
Wide Range ◽  
Anti Inflammatory

Antimicrobial peptides have broad-spectrum killing activities against bacteria, enveloped viruses, fungi and several parasites via cell membrane permeation and exhibit primarily immunomodulatory and anti-infective functions in their interactions with host cells. However, the mechanism underlying their anti-inflammatory activity remains to be elucidated. L-K6, an analog of temporin-1CEb isolated from the skin secretion of Rana chensinensis, has demonstrated a wide range of antimicrobial activities against gram-negative and gram-positive bacteria. In this study, the potent anti-inflammatory mechanism of L-K6 and its analogs in lipopolysaccharide (LPS)-stimulated human macrophage U937 cells were evaluated. We found that L-K6 suppressed the expression of inflammatory factors by two downstream signaling components in the MyD88-dependent pathway, including the mitogen-activated protein kinases (MAPKs) and the NF (nuclear factor)-κB signaling pathway, but its analog L-K5, which had the same amino acid sequence as L-K6 but no Lys residue at the –COOH terminal, only inhibited the phosphorylation of I-κB and NF-κB. Importantly, L-K6 and L-K5 were actively taken up by U937 cells through an independent cell membrane disruption mechanism and were eventually localized to the perinuclear region. The L-K6 uptake process was mediated by endocytosis, but L-K5 was specifically taken up by U937 cells via TLR4 endocytosis. Our results demonstrated that L-K6 can neutralize LPS and diassociate LPS micelles to inhibit LPS from triggering the proinflammatory signaling pathway, and by partially inhibiting inflammatory responses by the intracellular target. However, L-K5 may mainly inhibit proinflammatory responses by intracellular reporters to modulate the NF-κB signaling pathway.

scholarly journals A Protective Role of Aryl Hydrocarbon Receptor Repressor in Inflammation and Tumor Growth

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 589 ◽  
Author(s):  
Christoph F. A. Vogel ◽  
Yasuhiro Ishihara ◽  
Claire E. Campbell ◽  
Sarah Y. Kado ◽  
Aimy Nguyen-Chi ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Aryl Hydrocarbon Receptor ◽  
Inflammatory Responses ◽  
Environmental Pollutants ◽  
Protective Role ◽  
Potential Therapeutic Target ◽  
Embryonic Fibroblasts ◽  
Aryl Hydrocarbon ◽  
Enhancer Binding Protein

The aryl hydrocarbon receptor (AhR) is known for mediating the toxicity of environmental pollutants such as dioxins and numerous dioxin-like compounds, and is associated with the promotion of various malignancies, including lymphoma. The aryl hydrocarbon receptor repressor (AhRR), a ligand-independent, transcriptionally inactive AhR-like protein is known to repress AhR signaling through its ability to compete with the AhR for dimerization with the AhR nuclear translocator (ARNT). While AhRR effectively blocks AhR signaling, several aspects of the mechanism of AhRR’s functions are poorly understood, including suppression of inflammatory responses and its putative role as a tumor suppressor. In a transgenic mouse that overexpresses AhRR (AhRR Tg) we discovered that these mice suppress 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)- and inflammation-induced tumor growth after subcutaneous challenge of EL4 lymphoma cells. Using mouse embryonic fibroblasts (MEF) we found that AhRR overexpression suppresses the AhR-mediated anti-apoptotic response. The AhRR-mediated inhibition of apoptotic resistance was associated with a suppressed expression of interleukin (IL)-1β and cyclooxygenase (COX)-2, which was dependent on activation of protein kinase A (PKA) and the CAAT-enhancer-binding protein beta (C/EBPβ). These results provide mechanistic insights into the role of the AhRR to suppress inflammation and highlight the AhRR as a potential therapeutic target to suppress tumor growth.

scholarly journals The Role of the Aryl Hydrocarbon Receptor (AHR) in Immune and Inflammatory Diseases

2018 ◽  
Vol 19 (12) ◽  
pp. 3851 ◽  
Author(s):  
Drew Neavin ◽  
Duan Liu ◽  
Balmiki Ray ◽  
Richard Weinshilboum
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Nuclear Receptor ◽  
Binding Sites ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Dependent Manner ◽  
Nucleotide Polymorphisms ◽  
Aryl Hydrocarbon ◽  
Inflammatory Processes ◽  
Targeted Gene Expression

The aryl hydrocarbon receptor (AHR) is a nuclear receptor that modulates the response to environmental stimuli. It was recognized historically for its role in toxicology but, in recent decades, it has been increasingly recognized as an important modulator of disease—especially for its role in modulating immune and inflammatory responses. AHR has been implicated in many diseases that are driven by immune/inflammatory processes, including major depressive disorder, multiple sclerosis, rheumatoid arthritis, asthma, and allergic responses, among others. The mechanisms by which AHR has been suggested to impact immune/inflammatory diseases include targeted gene expression and altered immune differentiation. It has been suggested that single nucleotide polymorphisms (SNPs) that are near AHR-regulated genes may contribute to AHR-dependent disease mechanisms/pathways. Further, we have found that SNPs that are outside of nuclear receptor binding sites (i.e., outside of AHR response elements (AHREs)) may contribute to AHR-dependent gene regulation in a SNP- and ligand-dependent manner. This review will discuss the evidence and mechanisms of AHR contributions to immune/inflammatory diseases and will consider the possibility that SNPs that are outside of AHR binding sites might contribute to AHR ligand-dependent inter-individual variation in disease pathophysiology and response to pharmacotherapeutics.

scholarly journals M. tuberculosis infection of human iPSC-derived macrophages reveals complex membrane dynamics during xenophagy evasion

2020 ◽  
Vol 134 (5) ◽  
pp. jcs252973
Author(s):  
Elliott M. Bernard ◽  
Antony Fearns ◽  
Claudio Bussi ◽  
Pierre Santucci ◽  
Christopher J. Peddie ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Ion Beam ◽  
Induced Pluripotent Stem Cell ◽  
Membrane Dynamics ◽  
Live Cell ◽  
Initiation Factor ◽  
Human Macrophage ◽  
Transcriptional Responses ◽  
Macrophage Response ◽  
Human Macrophages

ABSTRACTXenophagy is an important cellular defence mechanism against cytosol-invading pathogens, such as Mycobacterium tuberculosis (Mtb). Activation of xenophagy in macrophages targets Mtb to autophagosomes; however, how Mtb is targeted to autophagosomes in human macrophages at a high spatial and temporal resolution is unknown. Here, we use human induced pluripotent stem cell-derived macrophages (iPSDMs) to study the human macrophage response to Mtb infection and the role of the ESX-1 type VII secretion system. Using RNA-seq, we identify ESX-1-dependent transcriptional responses in iPSDMs after infection with Mtb. This analysis revealed differential inflammatory responses and dysregulated pathways such as eukaryotic initiation factor 2 (eIF2) signalling and protein ubiquitylation. Moreover, live-cell imaging revealed that Mtb infection in human macrophages induces dynamic ESX-1-dependent, LC3B-positive tubulovesicular autophagosomes (LC3-TVS). Through a correlative live-cell and focused ion beam scanning electron microscopy (FIB SEM) approach, we show that upon phagosomal rupture, Mtb induces the formation of LC3-TVS, from which the bacterium is able to escape to reside in the cytosol. Thus, iPSDMs represent a valuable model for studying spatiotemporal dynamics of human macrophage–Mtb interactions, and Mtb is able to evade capture by autophagic compartments.

Tu1738 - The Aryl Hydrocarbon Receptor Mediates Anti-Inflammatory Activities of Natural and Synthetic Pelargonidines in Mouse Models of Colitis

2018 ◽  
Vol 154 (6) ◽  
pp. S-1006
Author(s):  
Adriana Carino ◽  
Michele Biagioli ◽  
Silvia Marchianò ◽  
Eleonora Distrutti ◽  
Chiara Fiorucci ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Mouse Models ◽  
Aryl Hydrocarbon ◽  
Anti Inflammatory ◽  
Natural And Synthetic

Activation of the aryl hydrocarbon receptor increases pulmonary neutrophilia and diminishes host resistance to influenza A virus

2005 ◽  
Vol 289 (1) ◽  
pp. L111-L124 ◽  
Author(s):  
Sabine Teske ◽  
Andrea A. Bohn ◽  
Jean F. Regal ◽  
Joshua J. Neumiller ◽  
B. Paige Lawrence
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Influenza A Virus ◽  
Influenza A ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Neutrophil Function ◽  
Aryl Hydrocarbon ◽  
Potent Agonist

Unlike their role in bacterial infection, less is known about the role of neutrophils during pulmonary viral infection. Exposure to pollutant 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD, dioxin) results in excess neutrophils in the lungs of mice infected with influenza A virus. TCDD is the most potent agonist for the aryl hydrocarbon receptor (AhR), and exposure to AhR ligands has been correlated with exacerbated inflammatory lung diseases. However, knowledge of the effects of AhR agonists on neutrophils is limited. Likewise, the factors regulating neutrophil responses during respiratory viral infections are not well characterized. To address these knowledge gaps, we determined the in vivo levels of KC, MIP-1α, MIP-2, LIX, IL-6, and C5a in infected mouse lungs. Our data show that these neutrophil chemoattractants are generally produced transiently in the lung within 12–24 h of infection. We also report that expression of CD11a, CD11b, CD49d, CD31, and CD38 is increased on pulmonary neutrophils in response to influenza virus. Using AhR-deficient mice, we demonstrate that excess neutrophilia in the lung is mediated by activation of the AhR and that this enhanced neutrophilia correlates directly with decreased survival in TCDD-exposed mice. Although AhR activation results in more neutrophils in the lungs, we show that this is not mediated by deregulation in levels of common neutrophil chemoattractants, expression of adhesion molecules on pulmonary neutrophils, or delayed death of neutrophils. Likewise, exposure to TCDD did not enhance pulmonary neutrophil function. This study provides an important first step in elucidating the mechanisms by which AhR agonists exacerbate pulmonary inflammatory responses.

scholarly journals Novel Human Lung Tissue Model for the Study of SARS-CoV-2 Entry, Inflammation and New Therapeutics

2021 ◽  
Author(s):  
Judith Grau-Expósito ◽  
David Perea ◽  
Marina Suppi ◽  
Núria Massana ◽  
Ander Vergara ◽  
...  
Keyword(s):  
Lung Tissue ◽  
Viral Entry ◽  
Human Lung ◽  
Inflammatory Responses ◽  
Alveolar Type ◽  
List Type ◽  
Human Lung Tissue ◽  
Main Cell ◽  
Anti Inflammatory ◽  
Conventional Systems

AbstractThe development of physiological models that reproduce SARS-CoV-2 infection in primary human cells will be instrumental to identify host-pathogen interactions and potential therapeutics. Here, using cell suspensions from primary human lung tissues (HLT), we have developed a platform for the identification of viral targets and the expression of viral entry factors, as well as for the screening of viral entry inhibitors and anti-inflammatory compounds. We show that the HLT model preserves its main cell populations, maintains the expression of proteins required for SARS-CoV-2 infection, and identifies alveolar type II (AT-II) cells as the most susceptible cell targets for SARS-CoV-2 in the human lung. Antiviral testing of 39 drug candidates revealed a highly reproducible system, and provided the identification of new compounds missed by conventional systems such as VeroE6. Using this model, we also show that interferons do not modulate ACE2 expression, and that stimulation of local inflammatory responses can be modulated by different compounds with antiviral activity. Overall, we present a novel and relevant physiological model for the study of SARS-CoV-2.SynopsisEx vivo physiological systems for the study of SARS-CoV-2-host interactions are scarce. Here, we establish a novel model using primary human lung tissue (HLT) for the analysis of cell tropism and identification of therapeutics.The HLT model preserves main cell subpopulations, including alveolar type-2 cells, and expression of SARS-CoV-2 entry factors ACE2, CD147, and TMPRSS2.The HLT model is readily susceptible to SARS-CoV-2 entry.Antiviral testing in the HLT model allows the identification of new candidates missed by conventional systems.Local inflammation is supported in the HLT model and offers the identification of relevant anti-inflammatory compounds for SARS-CoV-2 infection.

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