Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses

Exposure to microgravity conditions causes cardiovascular deconditioning in astronauts during spaceflight. Until now, no specific drugs are available for countermeasure, since the underlying mechanism is largely unknown. Endothelial cells (ECs) and smooth muscle cells (SMCs) play key roles in various vascular functions, many of which are regulated by purinergic 2 (P2) receptors. However, their function in ECs and SMCs under microgravity conditions is still unclear. In this study, primary ECs and SMCs were isolated from bovine aorta and verified with specific markers. We show for the first time that the P2 receptor expression pattern is altered in ECs and SMCs after 24 h exposure to simulated microgravity using a clinostat. However, conditioned medium compensates this change in specific P2 receptors, for example, P2X7. Notably, P2 receptors such as P2X7 might be the important players during the paracrine interaction. Additionally, ECs and SMCs secreted different cytokines under simulated microgravity, leading into a pathogenic proliferation and migration. In conclusion, our data indicate P2 receptors might be important players responding to gravity changes in ECs and SMCs. Since some artificial P2 receptor ligands are applied as drugs, it is reasonable to assume that they might be promising candidates against cardiovascular deconditioning in the future.

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Immunoregulation through extracellular nucleotides

Blood ◽

10.1182/blood-2012-01-406496 ◽

2012 ◽

Vol 120 (3) ◽

pp. 511-518 ◽

Cited By ~ 80

Author(s):

Laura Vitiello ◽

Stefania Gorini ◽

Giuseppe Rosano ◽

Andrea la Sala

Keyword(s):

Inflammatory Responses ◽

Receptor Expression ◽

Extracellular Nucleotides ◽

P2 Receptor ◽

Murine Models ◽

Danger Signal ◽

Chronic Stimulation ◽

P2 Purinergic Receptors ◽

Human Immune

Abstract Extracellular ATP (eATP), the most abundant among nucleotides, can act as a mediator during inflammatory responses by binding to plasmamembrane P2 purinergic receptors, which are widely expressed on cells of the immune system. eATP is generally considered as a classical danger signal, which stimulates immune responses in the presence of tissue damage. Converging evidence from several studies using murine models of chronic inflammation have supported this hypothesis; however, the role of eATP in the regulation of human immune function appears to be more complex. Chronic stimulation with micromolar eATP concentrations inhibits the proliferation of T and NK lymphocytes and enhances the capacity of dendritic cells to promote tolerance. The effect of eATP depends on multiple factors, such as the extent of stimulation, eATP concentration, presence/absence of other mediators in the microenvironment, and pattern of P2 receptor engagement. Small but significant differences in the pattern of P2 receptor expression in mice and humans confer the diverse capacities of ATP in regulating the immune response. Such diversity, which is often overlooked, should therefore be carefully considered when evaluating the role of eATP in human inflammatory and autoimmune diseases.

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Targeting Mononuclear Phagocyte Receptors in Cancer Immunotherapy: New Perspectives of the Triggering Receptor Expressed on Myeloid Cells (TREM-1)

Cancers ◽

10.3390/cancers12051337 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1337

Author(s):

Federica Raggi ◽

Maria Bosco

Keyword(s):

Tumor Progression ◽

Cancer Immunotherapy ◽

Inflammatory Responses ◽

Inflammatory Cells ◽

Therapeutic Strategies ◽

Mononuclear Phagocyte ◽

Mononuclear Phagocytes ◽

Receptor Expression ◽

Tumor Phenotype

Inflammatory cells are major players in the onset of cancer. The degree of inflammation and type of inflammatory cells in the tumor microenvironment (TME) are responsible for tilting the balance between tumor progression and regression. Cancer-related inflammation has also been shown to influence the efficacy of conventional therapy. Mononuclear phagocytes (MPs) represent a major component of the inflammatory circuit that promotes tumor progression. Despite their potential to activate immunosurveillance and exert anti-tumor responses, MPs are subverted by the tumor to support its growth, immune evasion, and spread. MP responses in the TME are dictated by a network of stimuli integrated through the cross-talk between activatory and inhibitory receptors. Alterations in receptor expression/signaling can create excessive inflammation and, when chronic, promote tumorigenesis. Research advances have led to the development of new therapeutic strategies aimed at receptor targeting to induce a tumor-infiltrating MP switch from a cancer-supportive toward an anti-tumor phenotype, demonstrating efficacy in different human cancers. This review provides an overview of the role of MP receptors in inflammation-mediated carcinogenesis and discusses the most recent updates regarding their targeting for immunotherapeutic purposes. We focus in particular on the TREM-1 receptor, a major amplifier of MP inflammatory responses, highlighting its relevance in the development and progression of several types of inflammation-associated malignancies and the promises of its inhibition for cancer immunotherapy.

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NTPDase8 protects mice from intestinal inflammation by limiting P2Y6 receptor activation: identification of a new pathway of inflammation for the potential treatment of IBD

Gut ◽

10.1136/gutjnl-2020-320937 ◽

2021 ◽

pp. gutjnl-2020-320937

Author(s):

Mabrouka Salem ◽

Joanna Lecka ◽

Julie Pelletier ◽

Danielle Gomes Marconato ◽

Aline Dumas ◽

...

Keyword(s):

Bone Marrow ◽

Epithelial Cells ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Receptor Activation ◽

Receptor Expression ◽

Nucleoside Triphosphate ◽

Dependent Manner ◽

P2 Receptor

ObjectiveNucleotides are danger signals that activate inflammatory responses via binding P2 receptors. The nucleoside triphosphate diphosphohydrolase-8 (NTPDase8) is an ectonucleotidase that hydrolyses P2 receptor ligands. We investigated the role of NTPDase8 in intestinal inflammation.DesignWe generated NTPDase8-deficient (Entpd8–/–) mice to define the role of NTPDase8 in the dextran sodium sulfate (DSS) colitis model. To assess inflammation, colons were collected and analysed by histopathology, reverse transcriptase-quantitative real-time PCR (RT-qPCR) and immunohistochemistry. P2 receptor expression was analysed by RT-qPCR on primary intestinal epithelium and NTPDase8 activity by histochemistry. The role of intestinal P2Y6 receptors was assessed by bone marrow transplantation experiments and with a P2Y6 receptor antagonist.ResultsNTPDase8 is the dominant enzyme responsible for the hydrolysis of nucleotides in the lumen of the colon. Compared with wild-type (WT) control mice, the colon of Entpd8–/– mice treated with DSS displayed significantly more histological damage, immune cell infiltration, apoptosis and increased expression of several proinflammatory cytokines. P2Y6 was the dominant P2Y receptor expressed at the mRNA level by the colonic epithelia. Irradiated P2ry6–/– mice transplanted with WT bone marrow were fully protected from DSS-induced intestinal inflammation. In agreement, the daily intrarectal injection of a P2Y6 antagonist protected mice from DSS-induced intestinal inflammation in a dose-dependent manner. Finally, human intestinal epithelial cells express NTPDase8 and P2Y6 similarly as in mice.ConclusionNTPDase8 protects the intestine from inflammation most probably by limiting the activation of P2Y6 receptors in colonic epithelial cells. This may provide a novel therapeutic strategy for the treatment of inflammatory bowel disease.

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P2 receptor expression signaling and function in osteoclasts

Frontiers in Bioscience ◽

10.2741/s214 ◽

2011 ◽

Vol S3 (3) ◽

pp. 1101-1118

Author(s):

S. Jeffrey Dixon

Keyword(s):

Receptor Expression ◽

P2 Receptor ◽

And Function

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Modulation of Macrophages M1/M2 Polarization Using Carbohydrate-Functionalized Polymeric Nanoparticles

Polymers ◽

10.3390/polym13010088 ◽

2020 ◽

Vol 13 (1) ◽

pp. 88

Author(s):

Raquel G. D. Andrade ◽

Bruno Reis ◽

Benjamin Costas ◽

Sofia A. Costa Lima ◽

Salette Reis

Keyword(s):

Inflammatory Responses ◽

Polymeric Nanoparticles ◽

Interaction Mechanism ◽

Mannose Receptor ◽

The Body ◽

Receptor Expression ◽

Production Methods ◽

Polymeric Nanocarriers ◽

Efficient Delivery

Exploiting surface endocytosis receptors using carbohydrate-conjugated nanocarriers brings outstanding approaches to an efficient delivery towards a specific target. Macrophages are cells of innate immunity found throughout the body. Plasticity of macrophages is evidenced by alterations in phenotypic polarization in response to stimuli, and is associated with changes in effector molecules, receptor expression, and cytokine profile. M1-polarized macrophages are involved in pro-inflammatory responses while M2 macrophages are capable of anti-inflammatory response and tissue repair. Modulation of macrophages’ activation state is an effective approach for several disease therapies, mediated by carbohydrate-coated nanocarriers. In this review, polymeric nanocarriers targeting macrophages are described in terms of production methods and conjugation strategies, highlighting the role of mannose receptor in the polarization of macrophages, and targeting approaches for infectious diseases, cancer immunotherapy, and prevention. Translation of this nanomedicine approach still requires further elucidation of the interaction mechanism between nanocarriers and macrophages towards clinical applications.

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Immunoreactivity for glial fibrillary acidic protein and P2 receptor expression on astrocytes in vivo

Drug Development Research ◽

10.1002/ddr.10216 ◽

2003 ◽

Vol 59 (1) ◽

pp. 175-189 ◽

Cited By ~ 8

Author(s):

Heike Franke ◽

Ute Krügel ◽

Jens Grosche ◽

Peter Illes

Keyword(s):

Glial Fibrillary Acidic Protein ◽

Receptor Expression ◽

Acidic Protein ◽

P2 Receptor

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Caffeine modulates brain purinergic signaling in Nile tilapia (Oreochromis niloticus) under hypoxia conditions: improvement of immune and inflammatory responses

Fish Physiology and Biochemistry ◽

10.1007/s10695-018-0592-z ◽

2018 ◽

Vol 45 (2) ◽

pp. 551-560

Author(s):

Matheus D. Baldissera ◽

Carine F. Souza ◽

Sharine N. Descovi ◽

Tiago G. Petrolli ◽

Aleksandro S. da Silva ◽

...

Keyword(s):

Oreochromis Niloticus ◽

Nile Tilapia ◽

Inflammatory Responses ◽

Purinergic Signaling ◽

Nile Tilapia Oreochromis Niloticus

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Mitochondrial DNA as an inflammatory mediator in cardiovascular diseases

Biochemical Journal ◽

10.1042/bcj20170714 ◽

2018 ◽

Vol 475 (5) ◽

pp. 839-852 ◽

Cited By ~ 39

Author(s):

Hiroyuki Nakayama ◽

Kinya Otsu

Keyword(s):

Mitochondrial Dna ◽

Inflammatory Responses ◽

Inflammatory Cells ◽

Nuclear Factor Κb ◽

Sterile Inflammation ◽

Microbial Infection ◽

Cellular Functions ◽

Radical Oxygen Species ◽

Cardiac Inflammation ◽

Contraction And Relaxation

Mitochondria play a central role in multiple cellular functions, including energy production, calcium homeostasis, and cell death. Currently, growing evidence indicates the vital roles of mitochondria in triggering and maintaining inflammation. Chronic inflammation without microbial infection — termed sterile inflammation — is strongly involved in the development of heart failure. Sterile inflammation is triggered by the activation of pattern recognition receptors (PRRs) that sense endogenous ligands called damage-associated molecular patterns (DAMPs). Mitochondria release multiple DAMPs including mitochondrial DNA, peptides, and lipids, which induce inflammation via the stimulation of multiple PRRs. Among the mitochondrial DAMPs, mitochondrial DNA (mtDNA) is currently highlighted as the DAMP that mediates the activation of multiple PRRs, including Toll-like receptor 9, Nod-like receptors, and cyclic GMP–AMP synthetase/stimulator of interferon gene pathways. These PRR signalling pathways, in turn, lead to the activation of nuclear factor-κB and interferon regulatory factor, which enhances the transcriptional activity of inflammatory cytokines and interferons, and induces the recruitment of inflammatory cells. As the heart is an organ comprising abundant mitochondria for its ATP consumption (needed to maintain constant cyclic contraction and relaxation), the generation of massive amounts of mitochondrial radical oxygen species and mitochondrial DAMPs are predicted to occur and promote cardiac inflammation. Here, we will focus on the role of mtDNA in cardiac inflammation and review the mechanism and pathological significance of mtDNA-induced inflammatory responses in cardiac diseases.

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Suppression of arthritis by an inhibitor of nitric oxide synthase.

Journal of Experimental Medicine ◽

10.1084/jem.178.2.749 ◽

1993 ◽

Vol 178 (2) ◽

pp. 749-754 ◽

Cited By ~ 437

Author(s):

N McCartney-Francis ◽

J B Allen ◽

D E Mizel ◽

J E Albina ◽

Q W Xie ◽

...

Keyword(s):

Nitric Oxide ◽

Inflammatory Responses ◽

Inflammatory Cells ◽

No Production ◽

Streptococcal Cell Wall ◽

Cell Mediated Immune Response ◽

A Cell ◽

Nos Inhibitor ◽

Oxide Synthase ◽

Articular Index

Nitric oxide (NO), a toxic radical gas produced during the metabolism of L-arginine by NO synthase (NOS), has been implicated as a mediator of immune and inflammatory responses. A single injection of streptococcal cell wall fragments (SCW) induces the accumulation of inflammatory cells within the synovial tissue and a cell-mediated immune response that leads destructive lesions. We show here that NO production is elevated in the inflamed joints of SCW-treated rats. Administration of NG-monomethyl-L-arginine, an inhibitor of NOS, profoundly reduced the synovial inflammation and tissue damage as measured by an articular index and reflected in the histopathology. These studies implicate the NO pathway in the pathogenesis of an inflammatory arthritis and demonstrate the ability of a NOS inhibitor to modulate the disease.

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