Aspirin and P2Y12 Inhibitors in platelet-mediated activation of neutrophils and monocytes

2015 ◽  
Vol 114 (09) ◽  
pp. 478-789 ◽  
Author(s):  
Waltraud Schrottmaier ◽  
Julia Kral ◽  
Sigrun Badrnya ◽  
Alice Assinger
Keyword(s):  
Immune Responses ◽  
Antiplatelet Therapy ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cardiovascular Complications ◽  
P2y12 Inhibitors ◽  
Beneficial Effects ◽  
Cox Inhibitor ◽  
The Impact

SummaryPlatelets are key players in haemostasis and represent a pivotal link between inflammation, immunity and atherogenesis. Depending on the (patho)physiological environment platelets modulate various leukocyte functions via release of inflammatory mediators and direct cell-cell interactions. Elevated levels of circulating platelet-leukocyte aggregates are found in patients suffering from several thrombotic or inflammatory conditions. Platelet-monocyte and platelet-neutrophil interaction can trigger pro- and anti-inflammatory responses and modulate effector functions of all leukocyte subpopulations. These platelet-mediated immune responses have implications for the progression of cardiovascular diseases and also play a crucial role during infections, cancer, transplantations and other inflammatory diseases of several organs. Antiplatelet therapy including the COX inhibitor aspirin and/or ADP receptor P2Y12 inhibitors such as clopidogrel, prasugrel and ticagrelor are the therapy of choice for various cardiovascular complications. Both aspirin and P2Y12 inhibitors attenuate platelet-leukocyte interactions, thereby also modulating immune responses. This may have beneficial effects in some pathological conditions, while it might be detrimental in others. This review aims to summarise the current knowledge on platelet-leukocyte interactions and the impact of aspirin and P2Y12 inhibition on platelet-mediated immune responses and to give an overview on the effects of antiplatelet therapy on platelet-leukocyte interplay in various diseases.

scholarly journals The Role of Src Kinase in Macrophage-Mediated Inflammatory Responses

2012 ◽  
Vol 2012 ◽  
pp. 1-18 ◽  
Author(s):  
Se Eun Byeon ◽  
Young-Su Yi ◽  
Jueun Oh ◽  
Byong Chul Yoo ◽  
Sungyoul Hong ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune Responses ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Src Kinase ◽  
Multiple Roles ◽  
Cellular Migration ◽  
Pharmaceutical Drugs ◽  
Tyrosine Protein Kinase

Src kinase (Src) is a tyrosine protein kinase that regulates cellular metabolism, survival, and proliferation. Many studies have shown that Src plays multiple roles in macrophage-mediated innate immunity, such as phagocytosis, the production of inflammatory cytokines/mediators, and the induction of cellular migration, which strongly implies that Src plays a pivotal role in the functional activation of macrophages. Macrophages are involved in a variety of immune responses and in inflammatory diseases including rheumatoid arthritis, atherosclerosis, diabetes, obesity, cancer, and osteoporosis. Previous studies have suggested roles for Src in macrophage-mediated inflammatory responses; however, recently, new functions for Src have been reported, implying that Src functions in macrophage-mediated inflammatory responses that have not been described. In this paper, we discuss recent studies regarding a number of these newly defined functions of Src in macrophage-mediated inflammatory responses. Moreover, we discuss the feasibility of Src as a target for the development of new pharmaceutical drugs to treat macrophage-mediated inflammatory diseases. We provide insights into recent reports regarding new functions for Src that are related to macrophage-related inflammatory responses and the development of novel Src inhibitors with strong immunosuppressive and anti-inflammatory properties, which could be applied to various macrophage-mediated inflammatory diseases.

Nuclear receptor Nur77: its role in chronic inflammatory diseases

2021 ◽  
Author(s):  
Sanne C. Lith ◽  
Carlie J.M. de Vries
Keyword(s):  
Nuclear Receptor ◽  
Inflammatory Disease ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Experimental Models ◽  
Therapeutic Interventions ◽  
Alternative Mechanism ◽  
Signaling Complex

Abstract Nur77 is a nuclear receptor that has been implicated as a regulator of inflammatory disease. The expression of Nur77 increases upon stimulation of immune cells and is differentially expressed in chronically inflamed organs in human and experimental models. Furthermore, in a variety of animal models dedicated to study inflammatory diseases, changes in Nur77 expression alter disease outcome. The available studies comprise a wealth of information on the function of Nur77 in diverse cell types and tissues. Negative cross-talk of Nur77 with the NFκB signaling complex is an example of Nur77 effector function. An alternative mechanism of action has been established, involving Nur77-mediated modulation of metabolism in macrophages as well as in T cells. In this review, we summarize our current knowledge on the role of Nur77 in atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis. Detailed insight in the control of inflammatory responses will be essential in order to advance Nur77-targeted therapeutic interventions in inflammatory disease.

Abstract 19409: β2-Adrenergic Receptor Regulation of Innate Immune Responses Following Acute Myocardial Injury

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Laurel A Grisanti ◽  
Anna Gumpert ◽  
Joshua Gorsky ◽  
Ashley A Repas ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Immune Responses ◽  
Adrenergic Receptor ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cellular Migration ◽  
Chimeric Mouse ◽  
Ccr2 Expression ◽  
Β2 Adrenergic Receptor ◽  
The Impact

Inflammatory responses are important for cardiac remodeling and tissue repair after myocardial infarction (MI). The sympathetic nervous system is known to regulate immune responses, in large part through the β2-adrenergic receptor (β2AR), however the influence of β2AR in regulating the inflammatory response following MI is unknown. Thus, to examine the contribution of β2AR on immune cells following MI, wild-type (WT) mice were irradiated and then received β2ARKO or WT control bone marrow (BM) transplants to create immune cell-specific knockout (KO) animals. Lack of β2AR expression in BM resulted in 100% mortality from cardiac rupture within two weeks of receiving MI, in contrast to their WT counterparts that had ∼20% death. Granulocyte populations were sequestered in the spleen of β2ARKO chimeric mice resulting in reductions in post-MI infiltration of monocyte/macrophage, neutrophil and mast cell populations into the heart. Additionally, alterations in chemokine receptor levels, particularly CCR2, on BM resulted in decreased cellular migration, and use of a CCR2 antagonist in vivo recapitulated the β2ARKO chimeric mouse phenotype following MI. Administration of β2AR agonists in vitro and in vivo increased CCR2 expression and BM migration while β2AR antagonists decreased CCR2 expression and increased splenic leukocyte retention in vivo . Use of pepducins as allosteric modulators of β2AR signaling demonstrated the importance of β-arrestin-mediated signaling in increasing CCR2 expression and responses. The impact of β2AR deletion on BM cell CCR2 expression and migration, splenic retention of leukocytes and reciprocal cardiac leukocyte infiltration following MI could be reversed via lentivirus-mediated β2AR rescue in the β2ARKO BM prior to transplantation. These results demonstrate the critical role of β2AR in the regulation of CCR2 expression on hematopoietic cells and its importance in mounting an immune response to promote healing following acute cardiac injury.

scholarly journals Mutual Interplay of Host Immune System and Gut Microbiota in the Immunopathology of Atherosclerosis

2020 ◽  
Vol 21 (22) ◽  
pp. 8729 ◽  
Author(s):  
Chih-Fan Yeh ◽  
Ying-Hsien Chen ◽  
Sheng-Fu Liu ◽  
Hsien-Li Kao ◽  
Ming-Shiang Wu ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Cytokine Production ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Inflammasome Activation ◽  
Host Immune System ◽  
Gut Permeability ◽  
And Function ◽  
Progression Of Atherosclerosis

Inflammation is the key for the initiation and progression of atherosclerosis. Accumulating evidence has revealed that an altered gut microbiome (dysbiosis) triggers both local and systemic inflammation to cause chronic inflammatory diseases, including atherosclerosis. There have been some microbiome-relevant pro-inflammatory mechanisms proposed to link the relationships between dysbiosis and atherosclerosis such as gut permeability disruption, trigger of innate immunity from lipopolysaccharide (LPS), and generation of proatherogenic metabolites, such as trimethylamine N-oxide (TMAO). Meanwhile, immune responses, such as inflammasome activation and cytokine production, could reshape both composition and function of the microbiota. In fact, the immune system delicately modulates the interplay between microbiota and atherogenesis. Recent clinical trials have suggested the potential of immunomodulation as a treatment strategy of atherosclerosis. Here in this review, we present current knowledge regarding to the roles of microbiota in contributing atherosclerotic pathogenesis and highlight translational perspectives by discussing the mutual interplay between microbiota and immune system on atherogenesis.

scholarly journals Succinate Is an Inflammation-Induced Immunoregulatory Metabolite in Macrophages

Metabolites ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 372 ◽  
Author(s):  
Karl J. Harber ◽  
Kyra E. de Goede ◽  
Sanne G. S. Verberk ◽  
Elisa Meinster ◽  
Helga E. de Vries ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Cells ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Cell Phenotype ◽  
Independent Manner ◽  
Inflammatory Macrophages ◽  
Necrosis Factor

Immunometabolism revealed the crucial role of cellular metabolism in controlling immune cell phenotype and functions. Macrophages, key immune cells that support progression of numerous inflammatory diseases, have been well described as undergoing vast metabolic rewiring upon activation. The immunometabolite succinate particularly gained a lot of attention and emerged as a crucial regulator of macrophage responses and inflammation. Succinate was originally described as a metabolite that supports inflammation via distinct routes. Recently, studies have indicated that succinate and its receptor SUCNR1 can suppress immune responses as well. These apparent contradictory effects might be due to specific experimental settings and particularly the use of distinct succinate forms. We therefore compared the phenotypic and functional effects of distinct succinate forms and receptor mouse models that were previously used for studying succinate immunomodulation. Here, we show that succinate can suppress secretion of inflammatory mediators IL-6, tumor necrosis factor (TNF) and nitric oxide (NO), as well as inhibit Il1b mRNA expression of inflammatory macrophages in a SUCNR1-independent manner. We also observed that macrophage SUCNR1 deficiency led to an enhanced inflammatory response without addition of exogenous succinate. While our study does not reveal new mechanistic insights into how succinate elicits different inflammatory responses, it does indicate that the inflammatory effects of succinate and its receptor SUCNR1 in macrophages are clearly context dependent.

scholarly journals Acidic Mammalian Chitinase Negatively Affects Immune Responses during Acute and ChronicAspergillus fumigatusExposure

2018 ◽  
Vol 86 (7) ◽  
Author(s):  
Jaleesa M. Garth ◽  
Joseph J. Mackel ◽  
Kristen M. Reeder ◽  
Jonathan P. Blackburn ◽  
Chad W. Dunaway ◽  
...  
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
Asthma Severity ◽  
Immune Defense ◽  
Negative Regulator ◽  
Prostaglandin E ◽  
Fungal Cell ◽  
Content Type ◽  
Acidic Mammalian Chitinase ◽  
The Impact

ABSTRACTChitin is a polysaccharide that provides structure and rigidity to the cell walls of fungi and insects. Mammals possess multiple chitinases, which function to degrade chitin, thereby supporting a role for chitinases in immune defense. However, chitin degradation has been implicated in the pathogenesis of asthma. Here, we determined the impact of acidic mammalian chitinase (AMCase) (Chia) deficiency on host defense during acute exposure to the fungal pathogenAspergillus fumigatusas well as its contribution toA. fumigatus-associated allergic asthma. We demonstrate that chitin in the fungal cell wall was detected at low levels inA. fumigatusconidia, which emerged at the highest level during hyphal transition. In response to acuteA. fumigatuschallenge,Chia−/−mice unexpectedly demonstrated lowerA. fumigatuslung burdens at 2 days postchallenge. The lower fungal burden correlated with decreased lung interleukin-33 (IL-33) levels yet increased IL-1β and prostaglandin E2(PGE2) production, a phenotype that we reported previously to promote the induction of IL-17A and IL-22. During chronicA. fumigatusexposure, AMCase deficiency resulted in lower dynamic and airway lung resistance than in wild-type mice. Improved lung physiology correlated with attenuated levels of the proallergic chemokines CCL17 and CCL22. Surprisingly, examination of inflammatory responses during chronic exposure revealed attenuated IL-17A and IL-22 responses, but not type 2 responses, in the absence of AMCase. Collectively, these data suggest that AMCase functions as a negative regulator of immune responses during acute fungal exposure and is a contributor to fungal asthma severity, putatively via the induction of proinflammatory responses.

Osteopontin and Mucosal Protection

2006 ◽  
Vol 85 (5) ◽  
pp. 404-415 ◽  
Author(s):  
J. Sodek ◽  
A. Paes Batista Da Silva ◽  
R. Zohar
Keyword(s):  
Immune Cells ◽  
Barrier Function ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Biological Activities ◽  
Proteolytic Processing ◽  
Mucosal Inflammation ◽  
Tissue Destruction ◽  
Mucosal Tissues

Protection of mucosal tissues of the oral cavity, intestines, respiratory tract, and urogenital tract from the constant challenge of pathogens is achieved by the combined barrier function of the lining epithelia and specialized immune cells. Recent studies have indicated that osteopontin (OPN) has a pivotal role in the development of immune responses and in the tissue destruction and the subsequent repair processes associated with inflammatory diseases. While expression of OPN is increased in immune cells—including neutrophils, macrophages, T- and B-lymphocytes—and in epithelial, endothelial, and fibroblastic cells of inflamed tissues, deciphering the specific functions of OPN has been difficult. In part, this is due to the broad range of biological activities of OPN that are mediated by multiple receptors which recognize several signaling motifs whose activities are influenced by post-translational modifications and proteolytic processing of OPN. Understanding the role of OPN in mucosal inflammation is further complicated by its contributions to the barrier function of the lining epithelia and the complexity of the specialized mucosal immune system. In an attempt to provide some insights into the involvement of OPN in mucosal diseases, this review summarizes current knowledge of the biological activities of OPN involved in the development of inflammatory responses and in wound healing, and indicates how these activities may affect the protection of mucosal tissues.

scholarly journals Mechanisms Involved in Type II Macrophage Activation and Effector Functions

2021 ◽  
Author(s):  
◽  
Marie Clare Lydia Kharkrang
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
Surface Marker ◽  
Alternative Activation ◽  
Type Ii ◽  
Activated Macrophages ◽  
Phenotypic Properties ◽  
Anti Inflammatory ◽  
The Impact

<p>Autoimmunities are extremely difficult to treat and involved in their pathogenesis are pro-inflammatory immune responses redirected against one's own tissues. Studies in our lab have shown macrophages that are induced to become type II macrophages protect against an animal model of MS, experimental autoimmune encephalomyelitis (EAE), with protection due to immune deviation. Another way to deviate immune responses away from inflammation is by infection with the parasitic helminth Schistosoma mansoni, which also protects against EAE. The contribution of type II macrophages in this protection is unknown, as are the mechanisms involved in promoting the phenotype induced by type II activation. This project investigates key mechanisms involved in type II activation, while also elucidating the possible effect of schistosome exposure on the induction of this activation state. Using a validated model of type II activation in vitro, we compared the effects of schistosome immune complexes on various macrophage properties such as cytokine, surface marker and enzymatic profiles. This thesis identified that exposure to schistosome complexes induces a macrophage state with characteristics of two distinct activation states (type II and alternative activation), as well as completely novel characteristics. This activation state shows many phenotypic properties associated with immune regulation, and may have important consequences for understanding mechanisms involved in protection against inflammatory illnesses. We also investigated key mechanisms involved in the anti-inflammatory responses induced by type II activation. Cytokine, chemokine and surface marker profiles of macrophages were assessed in response to type II activation in vitro, with the main emphasis on determining the effects of IL-10 and CD40 on the type II activation phenotype and function. This investigation found that type II activated macrophages depend on low levels of CD40/CD40L signalling to polarise Th2 development, as the expression of receptors for Th2-inducing cytokines are significantly impaired in the absence of this interaction. This suggests an important role for the low but maintained levels of CD40 on type II activated macrophages, in aiding the deviation of immune responses, while maintaining Th2 polarization. We also suggest a suppressive role of CD40/CD40L in IL-10 production, which is a novel find. The requirement of new treatments for MS is escalating as more people are affected each year. The impact of MS on the quality of life is severe and long lasting. Having a greater understanding of the mechanisms involved in deviating pro-inflammatory or anti-inflammatory responses will enable the development of much more effective treatments and therapies in the future.</p>

scholarly journals Regulation of common neurological disorders by gut microbial metabolites

2021 ◽  
Author(s):  
Jeongho Park ◽  
Chang H. Kim
Keyword(s):  
Neurological Disorders ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Short Chain Fatty Acids ◽  
Autism Spectrum ◽  
Molecular Networks ◽  
Microbial Metabolites ◽  
Cns Diseases ◽  
The Impact

AbstractThe gut is connected to the CNS by immunological mediators, lymphocytes, neurotransmitters, microbes and microbial metabolites. A mounting body of evidence indicates that the microbiome exerts significant effects on immune cells and CNS cells. These effects frequently result in the suppression or exacerbation of inflammatory responses, the latter of which can lead to severe tissue damage, altered synapse formation and disrupted maintenance of the CNS. Herein, we review recent progress in research on the microbial regulation of CNS diseases with a focus on major gut microbial metabolites, such as short-chain fatty acids, tryptophan metabolites, and secondary bile acids. Pathological changes in the CNS are associated with dysbiosis and altered levels of microbial metabolites, which can further exacerbate various neurological disorders. The cellular and molecular mechanisms by which these gut microbial metabolites regulate inflammatory diseases in the CNS are discussed. We highlight the similarities and differences in the impact on four major CNS diseases, i.e., multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and autism spectrum disorder, to identify common cellular and molecular networks governing the regulation of cellular constituents and pathogenesis in the CNS by microbial metabolites.

scholarly journals Impact of STING Inflammatory Signaling during Intracellular Bacterial Infections

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 74
Author(s):  
Erika S. Guimarães ◽  
Fabio V. Marinho ◽  
Nina M. G. P. de Queiroz ◽  
Maísa M. Antunes ◽  
Sergio C. Oliveira
Keyword(s):  
Immune Responses ◽  
Bacterial Infections ◽  
Inflammatory Responses ◽  
Metabolic Reprogramming ◽  
Host Cells ◽  
Type I Interferons ◽  
Type I ◽  
Bacterial Survival ◽  
Inflammatory Profile ◽  
The Impact

The early detection of bacterial pathogens through immune sensors is an essential step in innate immunity. STING (Stimulator of Interferon Genes) has emerged as a key mediator of inflammation in the setting of infection by connecting pathogen cytosolic recognition with immune responses. STING detects bacteria by directly recognizing cyclic dinucleotides or indirectly by bacterial genomic DNA sensing through the cyclic GMP-AMP synthase (cGAS). Upon activation, STING triggers a plethora of powerful signaling pathways, including the production of type I interferons and proinflammatory cytokines. STING activation has also been associated with the induction of endoplasmic reticulum (ER) stress and the associated inflammatory responses. Recent reports indicate that STING-dependent pathways participate in the metabolic reprogramming of macrophages and contribute to the establishment and maintenance of a robust inflammatory profile. The induction of this inflammatory state is typically antimicrobial and related to pathogen clearance. However, depending on the infection, STING-mediated immune responses can be detrimental to the host, facilitating bacterial survival, indicating an intricate balance between immune signaling and inflammation during bacterial infections. In this paper, we review recent insights regarding the role of STING in inducing an inflammatory profile upon intracellular bacterial entry in host cells and discuss the impact of STING signaling on the outcome of infection. Unraveling the STING-mediated inflammatory responses can enable a better understanding of the pathogenesis of certain bacterial diseases and reveal the potential of new antimicrobial therapy.

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