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Cells
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Purinergic Signalling and Inflammation-Related Diseases
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Purinergic Signalling and Inflammation-Related Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (15 November 2021) | Viewed by 31436

Special Issue Editors

Dr. Tobias Engel

E-Mail Website
Guest Editor
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland
Interests: epilepsy; diagnosis; purinergic signaling; P2X7; microRNAs; Alzheimer’s disease
Dr. Eva María Jiménez-Mateos

E-Mail Website
Guest Editor
Trinity College Dublin, Dublin, Ireland
Interests: neuroscience; hypoxia; neonatal; neonatal encephalopathy; hypoxic-ischaemic encephalopathy; microRNA
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Miguel Diaz-Hernandez

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, Veterinary Faculty, Complutense University of Madrid, 28040 Madrid, Spain
Interests: neurodegenerative diseases; Alzheimer disease; huntington disease; epilepsia; neurotransmission; purinergic signaling; TNAP; ATP; P2X and P2Y receptors

Special Issue Information

Dear Colleagues,

Inflammation is not only an important defence mechanism of cells against tissue injury, but inflammatory processes are also recognized to be one of the main contributors to numerous human diseases. Extracellular purinergic signalling is mediated by purine nucleotides and nucleosides such as adenosine and adenosine-triphosphate (ATP). Once released into the extracellular space, these molecules activate specific receptors: P1 receptors, which respond to the nucleoside adenosine, and P2 receptors, which respond to nucleotides such as ATP. Compelling evidence accumulated over the past number of decades has demonstrated purinergic signalling to mediate a broad range of cellular functions in health and disease. Among these, inflammation has attracted the most attention as one of the main pathways by which purinergic signalling contributes to diseases. Much progress has been made in dissecting purinergic signalling cascades, and, most importantly, the use of highly specific drugs targeting different components of the purinergic system has provided compelling evidence for a causal role of purinergic signalling in almost every human pathological condition ranging from cancer, to bone diseases, to diabetes, and to diseases of the brain. This present Special Issue will provide a broad overview of how purinergic signalling regulates inflammatory pathways and the contribution of purinergic signalling to acute and chronic diseases.

Dr. Tobias Engel
Dr. Eva María Jiménez-Mateos
Prof. Miguel Diaz-Hernandez
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • purinergic signaling
  • release mechanisms
  • adenosine
  • extracellular nucleotides
  • extracellular nucleotide degradation
  • ectoenzymes
  • nucleoside and nucleotide receptors
  • inflammation
  • physiological processes and disease
  • inflammasome
  • cellular stress
  • interleukins

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Published Papers (6 papers)

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Editorial

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3 pages, 212 KiB  
Editorial
Purinergic Signalling and Inflammation-Related Diseases
by Tobias Engel, Eva María Jiménez-Mateos and Miguel Diaz-Hernandez
Cells 2022, 11(23), 3748; https://doi.org/10.3390/cells11233748 - 24 Nov 2022
Cited by 4 | Viewed by 1729
Abstract
While acute inflammation is widely accepted as an important response mechanism of cells against tissue injury, sustained inflammatory processes are increasingly recognized as one of the main contributors to numerous diseases, including central-nervous system (CNS)-related and non-CNS-related diseases such as depression, neurodegenerative diseases, [...] Read more.
While acute inflammation is widely accepted as an important response mechanism of cells against tissue injury, sustained inflammatory processes are increasingly recognized as one of the main contributors to numerous diseases, including central-nervous system (CNS)-related and non-CNS-related diseases such as depression, neurodegenerative diseases, type 2 diabetes, hypertension, cardiovascular diseases, chronic kidney disease, osteoporosis, and cancer [...] Full article
(This article belongs to the Special Issue Purinergic Signalling and Inflammation-Related Diseases)

Research

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17 pages, 1522 KiB  
Article
Circulating P2X7 Receptor Signaling Components as Diagnostic Biomarkers for Temporal Lobe Epilepsy
by Giorgia Conte, Aida Menéndez-Méndez, Sebastian Bauer, Hany El-Naggar, Mariana Alves, Annette Nicke, Norman Delanty, Felix Rosenow, David C. Henshall and Tobias Engel
Cells 2021, 10(9), 2444; https://doi.org/10.3390/cells10092444 - 16 Sep 2021
Cited by 23 | Viewed by 3292
Abstract
Circulating molecules have potential as biomarkers to support the diagnosis of epilepsy and to assist with differential diagnosis, for example, in conditions resembling epilepsy, such as in psychogenic non-epileptic seizures (PNES). The P2X7 receptor (P2X7R) is an important regulator of inflammation and mounting [...] Read more.
Circulating molecules have potential as biomarkers to support the diagnosis of epilepsy and to assist with differential diagnosis, for example, in conditions resembling epilepsy, such as in psychogenic non-epileptic seizures (PNES). The P2X7 receptor (P2X7R) is an important regulator of inflammation and mounting evidence supports its activation in the brain during epilepsy. Whether the P2X7R or P2X7R-dependent signaling molecules can be used as biomarkers of epilepsy has not been reported. P2X7R levels were analyzed by quantitative ELISA using plasma samples from controls and patients with temporal lobe epilepsy (TLE) or PNES. Moreover, blood cell P2X7R expression and P2X7R-dependent cytokine signature was measured following status epilepticus in P2X7R-EGFP reporter, wildtype, and P2X7R-knockout mice. P2X7R plasma levels were higher in TLE patients when compared with controls and patients with PNES. Plasma levels of the broad inflammatory marker protein C-Reactive protein (CRP) were similar between the three groups. Using P2X7R-EGFP reporter mice, we identified monocytes as the main blood cell type expressing P2X7R after experimentally evoked seizures. Finally, cytokine array analysis in P2X7R-deficient mice identified KC/GRO as a potential P2X7R-dependent plasma biomarker following status epilepticus and during epilepsy. Our data suggest that P2X7R signaling components may be a promising subclass of circulating biomarkers to support the diagnosis of epilepsy. Full article
(This article belongs to the Special Issue Purinergic Signalling and Inflammation-Related Diseases)
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13 pages, 2224 KiB  
Article
Deletion of P2X7 Receptor Decreases Basal Glutathione Level by Changing Glutamate-Glutamine Cycle and Neutral Amino Acid Transporters
by Hana Park and Ji-Eun Kim
Cells 2020, 9(4), 995; https://doi.org/10.3390/cells9040995 - 16 Apr 2020
Cited by 19 | Viewed by 3132
Abstract
Glutathione (GSH) is an endogenous tripeptide antioxidant that consists of glutamate-cysteine-glycine. GSH content is limited by the availability of glutamate and cysteine. Furthermore, glutamine is involved in the regulation of GSH synthesis via the glutamate–glutamine cycle. P2X7 receptor (P2X7R) is one of the [...] Read more.
Glutathione (GSH) is an endogenous tripeptide antioxidant that consists of glutamate-cysteine-glycine. GSH content is limited by the availability of glutamate and cysteine. Furthermore, glutamine is involved in the regulation of GSH synthesis via the glutamate–glutamine cycle. P2X7 receptor (P2X7R) is one of the cation-permeable ATP ligand-gated ion channels, which is involved in neuronal excitability, neuroinflammation and astroglial functions. In addition, P2X7R activation decreases glutamate uptake and glutamine synthase (GS) expression/activity. In the present study, we found that P2X7R deletion decreased the basal GSH level without altering GSH synthetic enzyme expressions in the mouse hippocampus. P2X7R deletion also increased expressions of GS and ASCT2 (a glutamine:cysteine exchanger), but diminished the efficacy of N-acetylcysteine (NAC, a GSH precursor) in the GSH level. SIN-1 (500 μM, a generator nitric oxide, superoxide and peroxynitrite), which facilitates the cystine–cysteine shuttle mediated by xCT (a glutamate/cystein:cystine/NAC antiporter), did not affect basal GSH concentration in WT and P2X7R knockout (KO) mice. However, SIN-1 effectively reduced the efficacy of NAC in GSH synthesis in WT mice, but not in P2X7R KO mice. Therefore, our findings indicate that P2X7R may be involved in the maintenance of basal GSH levels by regulating the glutamate–glutamine cycle and neutral amino acid transports under physiological conditions, which may be the defense mechanism against oxidative stress during P2X7R activation. Full article
(This article belongs to the Special Issue Purinergic Signalling and Inflammation-Related Diseases)
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21 pages, 4607 KiB  
Article
Opposing Effects of Adenosine and Inosine in Human Subcutaneous Fibroblasts May Be Regulated by Third Party ADA Cell Providers
by Carina Herman-de-Sousa, Ana Rita Pinheiro, Diogo Paramos-de-Carvalho, Maria Adelina Costa, Fátima Ferreirinha, Teresa Magalhães-Cardoso, Severino Ribeiro, Julie Pelletier, Jean Sévigny and Paulo Correia-de-Sá
Cells 2020, 9(3), 651; https://doi.org/10.3390/cells9030651 - 7 Mar 2020
Cited by 14 | Viewed by 4862
Abstract
Human subcutaneous fibroblasts (HSCF) challenged with inflammatory mediators release huge amounts of ATP, which rapidly generates adenosine. Given the nucleoside’s putative relevance in wound healing, dermal fibrosis, and myofascial pain, we investigated the role of its precursor, AMP, and of its metabolite, inosine, [...] Read more.
Human subcutaneous fibroblasts (HSCF) challenged with inflammatory mediators release huge amounts of ATP, which rapidly generates adenosine. Given the nucleoside’s putative relevance in wound healing, dermal fibrosis, and myofascial pain, we investigated the role of its precursor, AMP, and of its metabolite, inosine, in HSCF cells growth and collagen production. AMP (30 µM) was rapidly (t½ 3 ± 1 min) dephosphorylated into adenosine by CD73/ecto-5′-nucleotidase. Adenosine accumulation (t½ 158 ± 17 min) in the extracellular fluid reflected very low cellular adenosine deaminase (ADA) activity. HSCF stained positively against A2A and A3 receptors but were A1 and A2B negative. AMP and the A2A receptor agonist, CGS21680C, increased collagen production without affecting cells growth. The A2A receptor antagonist, SCH442416, prevented the effects of AMP and CGS21680C. Inosine and the A3 receptor agonist, 2Cl-IB-MECA, decreased HSCF growth and collagen production in a MRS1191-sensitive manner, implicating the A3 receptor in the anti-proliferative action of inosine. Incubation with ADA reproduced the inosine effect. In conclusion, adenosine originated from extracellular ATP hydrolysis favors normal collagen production by HSCF via A2A receptors. Inhibition of unpredicted inosine formation by third party ADA cell providers (e.g., inflammatory cells) may be a novel therapeutic target to prevent inappropriate dermal remodeling via A3 receptors activation. Full article
(This article belongs to the Special Issue Purinergic Signalling and Inflammation-Related Diseases)
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Review

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19 pages, 1330 KiB  
Review
Perinatal Brain Injury and Inflammation: Lessons from Experimental Murine Models
by Aisling Leavy and Eva M. Jimenez Mateos
Cells 2020, 9(12), 2640; https://doi.org/10.3390/cells9122640 - 8 Dec 2020
Cited by 22 | Viewed by 5198
Abstract
Perinatal brain injury or neonatal encephalopathy (NE) is a state of disturbed neurological function in neonates, caused by a number of different aetiologies. The most prominent cause of NE is hypoxic ischaemic encephalopathy, which can often induce seizures. NE and neonatal seizures are [...] Read more.
Perinatal brain injury or neonatal encephalopathy (NE) is a state of disturbed neurological function in neonates, caused by a number of different aetiologies. The most prominent cause of NE is hypoxic ischaemic encephalopathy, which can often induce seizures. NE and neonatal seizures are both associated with poor neurological outcomes, resulting in conditions such as cerebral palsy, epilepsy, autism, schizophrenia and intellectual disability. The current treatment strategies for NE and neonatal seizures have suboptimal success in effectively treating neonates. Therapeutic hypothermia is currently used to treat NE and has been shown to reduce morbidity and has neuroprotective effects. However, its success varies between developed and developing countries, most likely as a result of lack of sufficient resources. The first-line pharmacological treatment for NE is phenobarbital, followed by phenytoin, fosphenytoin and lidocaine as second-line treatments. While these drugs are mostly effective at halting seizure activity, they are associated with long-lasting adverse neurological effects on development. Over the last years, inflammation has been recognized as a trigger of NE and seizures, and evidence has indicated that this inflammation plays a role in the long-term neuronal damage experienced by survivors. Researchers are therefore investigating the possible neuroprotective effects that could be achieved by using anti-inflammatory drugs in the treatment of NE. In this review we will highlight the current knowledge of the inflammatory response after perinatal brain injury and what we can learn from animal models. Full article
(This article belongs to the Special Issue Purinergic Signalling and Inflammation-Related Diseases)
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24 pages, 1211 KiB  
Review
Regulation of Microglial Functions by Purinergic Mechanisms in the Healthy and Diseased CNS
by Peter Illes, Patrizia Rubini, Henning Ulrich, Yafei Zhao and Yong Tang
Cells 2020, 9(5), 1108; https://doi.org/10.3390/cells9051108 - 29 Apr 2020
Cited by 147 | Viewed by 11878
Abstract
Microglial cells, the resident macrophages of the central nervous system (CNS), exist in a process-bearing, ramified/surveying phenotype under resting conditions. Upon activation by cell-damaging factors, they get transformed into an amoeboid phenotype releasing various cell products including pro-inflammatory cytokines, chemokines, proteases, reactive oxygen/nitrogen [...] Read more.
Microglial cells, the resident macrophages of the central nervous system (CNS), exist in a process-bearing, ramified/surveying phenotype under resting conditions. Upon activation by cell-damaging factors, they get transformed into an amoeboid phenotype releasing various cell products including pro-inflammatory cytokines, chemokines, proteases, reactive oxygen/nitrogen species, and the excytotoxic ATP and glutamate. In addition, they engulf pathogenic bacteria or cell debris and phagocytose them. However, already resting/surveying microglia have a number of important physiological functions in the CNS; for example, they shield small disruptions of the blood–brain barrier by their processes, dynamically interact with synaptic structures, and clear surplus synapses during development. In neurodegenerative illnesses, they aggravate the original disease by a microglia-based compulsory neuroinflammatory reaction. Therefore, the blockade of this reaction improves the outcome of Alzheimer’s Disease, Parkinson’s Disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. The function of microglia is regulated by a whole array of purinergic receptors classified as P2Y12, P2Y6, P2Y4, P2X4, P2X7, A2A, and A3, as targets of endogenous ATP, ADP, or adenosine. ATP is sequentially degraded by the ecto-nucleotidases and 5′-nucleotidase enzymes to the almost inactive inosine as an end product. The appropriate selective agonists/antagonists for purinergic receptors as well as the respective enzyme inhibitors may profoundly interfere with microglial functions and reconstitute the homeostasis of the CNS disturbed by neuroinflammation. Full article
(This article belongs to the Special Issue Purinergic Signalling and Inflammation-Related Diseases)
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