scholarly journals miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine macrophage inflammatory responses

2009 ◽  
Vol 106 (37) ◽  
pp. 15819-15824 ◽  
Author(s):  
Gang Liu ◽  
Arnaud Friggeri ◽  
Yanping Yang ◽  
Young-Jun Park ◽  
Yuko Tsuruta ◽  
...  
Keyword(s):  
Feedback Loop ◽  
Inflammatory Responses ◽  
Inflammatory Cells ◽  
Negative Regulator ◽  
Microbial Pathogens ◽  
Cellular Activation ◽  
Mouse Macrophages ◽  
Non Coding Rnas ◽  
Maximal Induction

Toll-like receptors (TLRs) are major receptors that enable inflammatory cells to recognize invading microbial pathogens. MicroRNAs are small non-coding RNAs that play important regulatory roles in a variety of biological processes. In this study, we found that a microRNA, miR-147, was induced upon stimulation of multiple TLRs and functioned as a negative regulator of TLR-associated signaling events in murine macrophages. We first demonstrated that the NMES1 transcript was a functional primary miR-147. miR-147 was induced in LPS-stimulated mouse macrophages and under in vivo conditions in the lungs of LPS-treated mice. Expression of miR-147 was greater after cellular activation by TLR4 than after engagement of either TLR2 or TLR3, suggesting that maximal induction of miR-147 required activation of both NF-κB and IRF3. TLR4-induced miR-147 expression was both MyD88- and TRIF-dependent. The miR-147 promoter was responsive to TLR4 stimulation and both NF-κB and STAT1α bound to the miR-147 promoter. miR-147 mimics or induced expression of miR-147 decreased, whereas miR-147 knockdown increased inflammatory cytokine expression in macrophages stimulated with ligands to TLR2, TLR3, and TLR4. These data demonstrate a negative-feedback loop in which TLR stimulation induces miR-147 to prevent excessive inflammatory responses.

Enhanced susceptibility of staggerer (RORαsg/sg) mice to lipopolysaccharide-induced lung inflammation

2005 ◽  
Vol 289 (1) ◽  
pp. L144-L152 ◽  
Author(s):  
Cliona M. Stapleton ◽  
Maisa Jaradat ◽  
Darlene Dixon ◽  
Hong Soon Kang ◽  
Seong-Chul Kim ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Inflammatory Responses ◽  
Inflammatory Cells ◽  
Negative Regulator ◽  
Orphan Receptor ◽  
Immune Functions ◽  
Wild Type ◽  
Lps Challenge ◽  
Inflammatory Protein

The retinoid-related orphan receptor α (RORα), a member of the ROR subfamily of nuclear receptors, has been implicated in the control of a number of physiological processes, including the regulation of several immune functions. To study the potential role of RORα in the regulation of innate immune responses in vivo, we analyzed the induction of airway inflammation in response to lipopolysaccharide (LPS) challenge in wild-type and staggerer (RORαsg/sg) mice, a natural mutant strain lacking RORα expression. Examination of hematoxylin and eosin-stained lung sections showed that RORαsg/sg mice displayed a higher degree of LPS-induced inflammation than wild-type mice. Bronchoalveolar lavage (BAL) was performed at 3, 16, and 24 h after LPS exposure to monitor the increase in inflammatory cells and the level of several cytokines/chemokines. The increased susceptibility of RORαsg/sg mice to LPS-induced airway inflammation correlated with a higher number of total cells and neutrophils in BAL fluids from LPS-treated RORαsg/sg mice compared with those from LPS-treated wild-type mice. In addition, IL-1β, IL-6, and macrophage inflammatory protein-2 were appreciably more elevated in BAL fluids from LPS-treated RORαsg/sg mice compared with those from LPS-treated wild-type mice. The enhanced susceptibility of RORαsg/sg mice appeared not to be due to a repression of IκBα expression. Our observations indicate that RORαsg/sg mice are more susceptible to LPS-induced airway inflammation and are in agreement with the hypothesis that RORα functions as a negative regulator of LPS-induced inflammatory responses.

Inhibition of monocyte-derived inflammatory cytokines by IL-25 occurs via p38 Map kinase–dependent induction of Socs-3

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3512-3519 ◽  
Author(s):  
Roberta Caruso ◽  
Carmine Stolfi ◽  
Massimiliano Sarra ◽  
Angelamaria Rizzo ◽  
Massimo C. Fantini ◽  
...  
Keyword(s):  
Map Kinase ◽  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Human Peripheral Blood ◽  
Serum Levels ◽  
Cell Types ◽  
P38 Map Kinase ◽  
Negative Regulator ◽  
Therapeutic Implications

Abstract IL-25, a member of the IL-17 cytokine family, is known to enhance Th2-like responses associated with increased serum levels of IgE, IgG1, IgA, blood eosinophilia, and eosinophilic infiltrates in various tissues. However, IL-25 also abrogates inflammatory responses driven by Th17 cells. However, the cell types that respond to IL-25 and the mechanisms by which IL-25 differentially regulates immune reactions are not well explored. To identify potential targets of IL-25, we initially examined IL-25 receptor (IL-25R) in human peripheral blood cells. IL-25R was predominantly expressed by CD14+ cells. We next assessed the functional role of IL-25 in modulating the response of CD14+ cells to various inflammatory signals. CD14+ cells responded to IL-25 by down-regulating the synthesis of inflammatory cytokines induced by toll-like receptor (TLR) ligands and inflammatory cytokines. Inhibition of cytokine response by IL-25 occurred via a p38 Map kinase–driven Socs-3–dependent mechanism. In vivo, IL-25 inhibited monocyte-derived cytokines and protected against LPS-induced lethal endotoxemia in mice. These data indicate that IL-25 is a negative regulator of monocyte proinflammatory cytokine responses, which may have therapeutic implications.

scholarly journals The Anti-Inflammatory Effects of Angiogenin in an Endotoxin Induced Uveitis in Rats

2020 ◽  
Vol 21 (2) ◽  
pp. 413
Author(s):  
Jihae Park ◽  
Jee Taek Kim ◽  
Soo Jin Lee ◽  
Jae Chan Kim
Keyword(s):  
Western Blot ◽  
Inflammatory Cytokines ◽  
Aqueous Humor ◽  
Rat Model ◽  
Inflammatory Responses ◽  
Inflammatory Cells ◽  
Ocular Tissue ◽  
Tnf Α ◽  
Anti Inflammatory

Angiogenin (ANG) is involved in the innate immune system and inflammatory disease. The aim of this study is to evaluate the anti-inflammatory effects of ANG in an endotoxin induced uveitis (EIU) rat model and the pathways involved. EIU rats were treated with balanced salt solution (BSS), a non-functional mutant ANG (mANG), or wild-type ANG (ANG). The integrity of the blood-aqueous barrier was evaluated by the infiltrating cell and protein concentrations in aqueous humor. Histopathology, Western blot, and real-time qRT-PCR of aqueous humor and ocular tissue were performed to analyze inflammatory cytokines and transcription factors. EIU treated with ANG had decreased inflammatory cells and protein concentrations in the anterior chamber. Compared to BSS and mANG, ANG treatment showed reduced expression of IL-1β, IL-8, TNF-α, and Myd88, while the expression of IL-4 and IL-10 was increased. Western blot of ANG treatment showed decreased expression of IL-6, inducible nitric oxide synthase (iNOS), IL-1β, TNF-α, and phosphorylated NF-κB and increased expression of IL-10. In conclusion, ANG seems to reduce effectively immune mediated inflammation in the EIU rat model by reducing the expression of proinflammatory cytokines, while increasing the expression of anti-inflammatory cytokines through pathways related to NF-κB. Therefore, ANG shows potential for effectively suppressing immune-inflammatory responses in vivo.

scholarly journals Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression

2016 ◽  
Vol 76 (3) ◽  
pp. 612-619 ◽  
Author(s):  
E A Ross ◽  
A J Naylor ◽  
J D O'Neil ◽  
T Crowley ◽  
M L Ridley ◽  
...  
Keyword(s):  
Inflammatory Arthritis ◽  
Inflammatory Responses ◽  
Vascular Endothelial Cells ◽  
Bone Erosion ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Critical Determinant ◽  
Anti Inflammatory

ObjectivesTristetraprolin (TTP), a negative regulator of many pro-inflammatory genes, is strongly expressed in rheumatoid synovial cells. The mitogen-activated protein kinase (MAPK) p38 pathway mediates the inactivation of TTP via phosphorylation of two serine residues. We wished to test the hypothesis that these phosphorylations contribute to the development of inflammatory arthritis, and that, conversely, joint inflammation may be inhibited by promoting the dephosphorylation and activation of TTP.MethodsThe expression of TTP and its relationship with MAPK p38 activity were examined in non-inflamed and rheumatoid arthritis (RA) synovial tissue. Experimental arthritis was induced in a genetically modified mouse strain, in which endogenous TTP cannot be phosphorylated and inactivated. In vitro and in vivo experiments were performed to test anti-inflammatory effects of compounds that activate the protein phosphatase 2A (PP2A) and promote dephosphorylation of TTP.ResultsTTP expression was significantly higher in RA than non-inflamed synovium, detected in macrophages, vascular endothelial cells and some fibroblasts and co-localised with MAPK p38 activation. Substitution of TTP phosphorylation sites conferred dramatic protection against inflammatory arthritis in mice. Two distinct PP2A agonists also reduced inflammation and prevented bone erosion. In vitro anti-inflammatory effects of PP2A agonism were mediated by TTP activation.ConclusionsThe phosphorylation state of TTP is a critical determinant of inflammatory responses, and a tractable target for novel anti-inflammatory treatments.

scholarly journals Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases

2014 ◽  
Vol 94 (2) ◽  
pp. 329-354 ◽  
Author(s):  
Asima Bhattacharyya ◽  
Ranajoy Chattopadhyay ◽  
Sankar Mitra ◽  
Sheila E. Crowe
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Inflammatory Cells ◽  
Cellular Level ◽  
Microbial Pathogens ◽  
Peptic Ulcers ◽  
Chronic Infections ◽  
Disease Pathogenesis

Reactive oxygen species (ROS) are generated as by-products of normal cellular metabolic activities. Superoxide dismutase, glutathione peroxidase, and catalase are the enzymes involved in protecting cells from the damaging effects of ROS. ROS are produced in response to ultraviolet radiation, cigarette smoking, alcohol, nonsteroidal anti-inflammatory drugs, ischemia-reperfusion injury, chronic infections, and inflammatory disorders. Disruption of normal cellular homeostasis by redox signaling may result in cardiovascular, neurodegenerative diseases and cancer. ROS are produced within the gastrointestinal (GI) tract, but their roles in pathophysiology and disease pathogenesis have not been well studied. Despite the protective barrier provided by the mucosa, ingested materials and microbial pathogens can induce oxidative injury and GI inflammatory responses involving the epithelium and immune/inflammatory cells. The pathogenesis of various GI diseases including peptic ulcers, gastrointestinal cancers, and inflammatory bowel disease is in part due to oxidative stress. Unraveling the signaling events initiated at the cellular level by oxidative free radicals as well as the physiological responses to such stress is important to better understand disease pathogenesis and to develop new therapies to manage a variety of conditions for which current therapies are not always sufficient.

scholarly journals PI(3)P-p40 phox binding regulates NADPH oxidase activation in mouse macrophages and magnitude of inflammatory responses in vivo

2016 ◽  
Vol 101 (2) ◽  
pp. 449-457 ◽  
Author(s):  
Juhi Bagaitkar ◽  
Emilia A. Barbu ◽  
Lizet J. Perez-Zapata ◽  
Anthony Austin ◽  
Guangming Huang ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Inflammatory Responses ◽  
Mouse Macrophages ◽  
Nadph Oxidase Activation

scholarly journals Modulation of experimental autoimmune encephalomyelitis through TRAF3-mediated suppression of interleukin 17 receptor signaling

2010 ◽  
Vol 207 (12) ◽  
pp. 2647-2662 ◽  
Author(s):  
Shu Zhu ◽  
Wen Pan ◽  
Peiqing Shi ◽  
Hanchao Gao ◽  
Fang Zhao ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Inflammatory Cytokine ◽  
Inflammatory Responses ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 17 ◽  
Receptor Signaling ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Interleukin 17 (IL-17) plays critical roles in the pathogenesis of various autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE). How the signals triggered by this powerful inflammatory cytokine are controlled to avoid abnormal inflammatory responses is not well understood. In this study, we report that TRAF3 is a receptor proximal negative regulator of IL-17 receptor (IL-17R) signaling. TRAF3 greatly suppressed IL-17–induced NF-κB and mitogen-activated protein kinase activation and subsequent production of inflammatory cytokines and chemokines. Mechanistically, the binding of TRAF3 to IL-17R interfered with the formation of the receptor signaling activation complex IL-17R–Act1–TRAF6, resulting in suppression of downstream signaling. TRAF3 markedly inhibited IL-17–induced expression of inflammatory cytokine and chemokine genes in vivo and consequently delayed the onset and greatly reduced the incidence and severity of EAE. Thus, TRAF3 is a negative regulator of IL-17R proximal signaling.

scholarly journals Modulation of Immune Complex–induced Inflammation In Vivo by the Coordinate Expression of Activation and Inhibitory Fc Receptors

1999 ◽  
Vol 189 (1) ◽  
pp. 179-186 ◽  
Author(s):  
Raphael Clynes ◽  
Jay S. Maizes ◽  
Rodolphe Guinamard ◽  
Masao Ono ◽  
Toshiyuki Takai ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Immune Complexes ◽  
Inflammatory Responses ◽  
Fc Receptors ◽  
Inflammatory Cells ◽  
Neutrophil Infiltration ◽  
Calcium Flux ◽  
Deficient Mice

Autoantibodies and immune complexes are major pathogenic factors in autoimmune injury, responsible for initiation of the inflammatory cascade and its resulting tissue damage. This activation results from the interaction of immunoglobulin (Ig)G Fc receptors containing an activation motif (ITAM) with immune complexes (ICs) and cytotoxic autoantibodies which initiates and propagates an inflammatory response. In vitro, this pathway can be interrupted by coligation to FcγRIIB, an IgG Fc receptor containing an inhibitory motif (ITIM). In this report, we describe the in vivo consequences of FcγRII deficiency in the inflammatory response using a mouse model of IC alveolitis. At subthreshold concentrations of ICs that fail to elicit inflammatory responses in wild-type mice, FcγRII-deficient mice developed robust inflammatory responses characterized by increased hemorrhage, edema, and neutrophil infiltration. Bronchoalveolar fluids from FcγRII−/− stimulated mice contain higher levels of tumor necrosis factor and chemotactic activity, suggesting that FcγRII deficiency lowers the threshold of IC stimulation of resident cells such as the alveolar macrophage. In contrast, complement- and complement receptor–deficient mice develop normal inflammatory responses to suprathreshold levels of ICs, while FcRγ−/− mice are completely protected from inflammatory injury. An inhibitory role for FcγRII on macrophages is demonstrated by analysis of FcγRII−/− macrophages which show greater phagocytic and calcium flux responses upon FcγRIII engagement. These data reveal contrasting roles for the cellular receptors for IgG on inflammatory cells, providing a regulatory mechanism for setting thresholds for IC sensitivity based on the ratio of ITIM to ITAM FcγR expression. Exploiting the FcγRII inhibitory pathway could thus provide a new therapeutic approach for modulating antibody-triggered inflammation.

scholarly journals Diflunisal targets the HMGB1/CXCL12 heterocomplex and blocks immune cell recruitment

2019 ◽  
Author(s):  
Federica De Leo ◽  
Giacomo Quilici ◽  
Mario Tirone ◽  
Valeria Mannella ◽  
Francesco De Marchis ◽  
...  
Keyword(s):  
Rational Design ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Inflammatory Cells ◽  
Cell Recruitment ◽  
Redox States ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

AbstractExtracellular HMGB1 triggers inflammation following infection or injury, and supports tumorigenesis in inflammation-related malignancies. HMGB1 has several redox states: reduced HMGB1 recruits inflammatory cells to injured tissues forming a heterocomplex with CXCL12 and signaling via its receptor CXCR4; disulfide-containing HMGB1 binds to TLR4 and promotes inflammatory responses. Here we show that Diflunisal, an aspirin-like nonsteroidal anti-inflammatory drug (NSAID) that has been in clinical use for decades, specifically inhibits in vitro and in vivo the chemotactic activity of HMGB1 at nanomolar concentrations, at least in part by binding directly to both HMGB1 and CXCL12 and disrupting their heterocomplex. Importantly, Diflunisal does not inhibit TLR4-dependent responses. Our findings clarify the mode of action of Diflunisal, and open the way to the rational design of functionally specific anti-inflammatory drugs.

Abstract 7: In vivo Transcriptional Profiling of Endothelial Cells Identifies Vascular Bed-Specific Changes Upon Lps-Induced Endotoxemia

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Audrey Cleuren ◽  
Martijn van der Ent ◽  
Kristina Hunker ◽  
Hui Jiang ◽  
Andrew Yee ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cellular Response ◽  
Inflammatory Responses ◽  
Differential Expression Analysis ◽  
Response To Therapy ◽  
Microbial Pathogens ◽  
P Value ◽  
Transcriptional Changes ◽  
Vascular Beds

Endothelial cells (ECs) form a critical barrier between blood and parenchymal cells and play an important role in many pathologic conditions, including sepsis. ECs are highly adaptive to their microenvironment and also act as a critical responder to microbial pathogens. Though ECs are thought to display extensive heterogeneity, detailed profiling of the in vivo EC gene expression program has been limited by the challenges of isolating ECs from complex tissues and the phenotypic drift associated with manipulation and expansion of ECs in vitro . We applied an in vivo system in which a conditional hemagglutinin-epitope tag is targeted into the mouse ribosomal protein Rpl22 locus and specifically activated in ECs, allowing immunoisolation of endothelial ribosome-associated mRNA. Both EC-selected and total mRNA from tissue lysates (brain, heart, kidney, liver and lung) were subjected to RNA sequencing followed by differential expression analysis to determine EC-enriched transcripts. These analyses were performed under physiologic conditions as well as in LPS injected mice to study transcriptional changes induced in ECs following endotoxin exposure. LPS-induced endotoxemia resulted in striking changes in the EC transcriptome (~800 per tissue), and included transcripts associated with known sepsis related pathophysiology, including impaired hemostasis, leukocyte recruitment and increased vascular permeability. Gene ontology analysis of transcriptional changes shared between ECs of different tissues identified cellular response to LPS among the highest enriched biologic processes (adjusted p-value 5.2E-5), together with immune (2.0E-14) and inflammatory responses (4.4E-12). Novel transcripts not previously associated with ECs or endotoxemia were also identified, as well as a subset of genes uniquely expressed in distinct vascular beds. In conclusion, our findings demonstrate remarkable heterogeneity of the EC transcriptome across multiple vascular beds in vivo . The EC response to endotoxin challenge is also highly heterogeneous across vascular beds and provides new insight into the endothelial response to infectious challenges, as well as identifying potentially useful biomarkers for the onset of sepsis and response to therapy.

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