Purinergic (P2X7) Receptor Activation of Microglia Induces Cell Death via an Interleukin-1-Independent Mechanism

doi:10.1006/mcne.2001.1054

Molecular and Cellular Neuroscience

Volume 19, Issue 2, February 2002, Pages 272-280

https://doi.org/10.1006/mcne.2001.1054 Get rights and content

Abstract

Activation of purinergic P2X7 receptors, principally by extracellular ATP, promotes the processing and release of the cytokine interleukin-1β (IL-1β) and induces cell death in activated microglia and macrophages. The objective of this study was to determine if IL-1β release contributes directly to this cell death in microglia. Exposure of microglia to bacterial lipopolysaccharide (LPS) and ATP induced release of IL-1β and IL-1α, as well as cell death. Neither cell death nor IL-1 release was observed in microglia lacking the P2X7 receptor. Microglia from mice lacking the IL-1β gene demonstrated a profile of death identical to that of wild-type microglia in response to LPS and ATP. Thus, IL-1β is not required for P2X7 receptor-stimulated microglial death.

References (40)

F. Di Virgilio
The P2z purinoceptor: An intriguing role in immunity, inflammation and cell death
Immunol. Today
(1995)
C.A. Dinarello
Biologic basis for interleukin-1 in disease
Blood
(1996)
D. Ferrari et al.
ATP-mediated cytotoxicity in microglial cells
Neuropharmacology
(1997)
M.M. Gabellec et al.
Analysis of brain mRNA by reverse transcription-polymerase chain reaction and hybridization with digoxigenin-labeled DNA probe
Brain Res. Brain Res. Protocols
(1997)
J. Honkaniemi et al.
Global ischemia induces apoptosis-associated genes in hippocampus
Brain Res. Mol. Brain Res.
(1996)
M. Imai et al.
CD39 modulates IL-1 release from activated endothelial cells
Biochem. Biophys. Res. Commun.
(2000)
G.W. Kreutzberg
Microglia: A sensor for pathological events in the CNS
Trends Neurosci.
(1996)
R.E. Laliberte et al.
ATP treatment of human monocytes promotes caspase-1 maturation and externalization
J. Biol. Chem.
(1999)
D. Martin et al.
Protective effect of the interleukin-1 receptor antagonist (IL-1ra) on experimental allergic encephalomyelitis in rats
J. Neuroimmunol.
(1995)
M. Mogi et al.
Interleukin-1b, interleukin-6, epidermal growth factor and transforming growth factor-a are elevated in the brain from parkinsonian patients
Neurosci. Lett.
(1994)

D. Perregaux et al.

Interleukin-1 beta maturation and release in response to ATP and nigericin. Evidence that potassium depletion mediated by these agents is a necessary and common feature of their activity

J. Biol. Chem.

(1994)

G. Raivich et al.

Neuroglial activation repertoire in the injured brain: Graded response, molecular mechanisms and cues to physiological function

Brain Res. Brain Res. Rev.

(1999)

N.J. Rothwell et al.

Cytokines and the nervous system. II. Actions and mechanisms of action

Trends Neurosci.

(1995)

N.J. Rothwell et al.

Interleukin 1 in the brain: Biology, pathology and therapeutic target

Trends Neurosci.

(2000)

M. Solle et al.

Altered cytokine production in mice lacking P2X7 receptors

J. Biol. Chem.

(2001)

M. Weibel et al.

Chemically defined medium for the rat astroglial cells in primary cultures

Int. J. Dev. Neurosci.

(1984)

S. Bhakdi et al.

Effects of Escherichia coli hemolysin on human monocytes. Cytocidal action and stimulation of interleukin 1 release

J. Clin. Invest.

(1990)

J. Carmichael et al.

Evaluation of a tetrazolium-based semiautomated colorimetric assay: Assessment of chemosensitivity testing

Cancer Res.

(1987)

G.R. Dubyak et al.

Signal transduction via P2-purinergic receptors for extracellular ATP and other nucleotides

Am. J. Physiol.

(1993)

Cited by (123)

The role of dopamine in NLRP3 inflammasome inhibition: Implications for neurodegenerative diseases
2023, Ageing Research Reviews
In the Central Nervous System (CNS), neuroinflammation orchestrated by microglia and astrocytes is an innate immune response to counteract stressful and dangerous insults. One of the most important and best characterized players in the neuroinflammatory response is the NLRP3 inflammasome, a multiproteic complex composed by NOD-like receptor family Pyrin domain containing 3 (NLRP3), apoptosis-associated speck–like protein (ASC) and pro-caspase-1. Different stimuli mediate NLRP3 activation, resulting in the NLRP3 inflammasome assembly and the pro-inflammatory cytokine (IL-1β and IL-18) maturation and secretion. The persistent and uncontrolled NLRP3 inflammasome activation has a leading role during the pathophysiology of neuroinflammation in age-related neurodegenerative diseases such as Parkinson’s (PD) and Alzheimer’s (AD). The neurotransmitter dopamine (DA) is one of the players that negatively modulate NLRP3 inflammasome activation through DA receptors expressed in both microglia and astrocytes. This review summarizes recent findings linking the role of DA in the modulation of NLRP3-mediated neuroinflammation in PD and AD, where early deficits of the dopaminergic system are well characterized. Highlighting the relationship between DA, its glial receptors and the NLRP3-mediated neuroinflammation can provide insights to novel diagnostic strategies in early disease phases and new pharmacological tools to delay the progression of these diseases.
Purinergic signaling in cognitive impairment and neuropsychiatric symptoms of Alzheimer's disease
2023, Neuropharmacology
About 10 million new cases of dementia develop worldwide each year, of which up to 70% are attributable to Alzheimer's disease (AD). In addition to the widely known symptoms of memory loss and cognitive impairment, AD patients frequently develop non-cognitive symptoms, referred to as behavioral and psychological symptoms of dementia (BPSDs). Sleep disorders are often associated with AD, but mood alterations, notably depression and apathy, comprise the most frequent class of BPSDs. BPSDs negatively affect the lives of AD patients and their caregivers, and have a significant impact on public health systems and the economy. Because treatments currently available for AD are not disease-modifying and mainly aim to ameliorate some of the cognitive symptoms, elucidating the mechanisms underlying mood alterations and other BPSDs in AD may reveal novel avenues for progress in AD therapy. Purinergic signaling is implicated in the pathophysiology of several central nervous system (CNS) disorders, such as AD, depression and sleep disorders. Here, we review recent findings indicating that purinergic receptors, mainly the A₁, A_2A, and P2X7 subtypes, are associated with the development/progression of AD. Current evidence suggests that targeting purinergic signaling may represent a promising therapeutic approach in AD and related conditions.
This article is part of the Special Issue on “Purinergic Signaling: 50 years”.
Purinergic ionotropic P2X7 and metabotropic glutamate mGlu<inf>5</inf> receptors crosstalk influences pro-inflammatory conditions in microglia
2023, European Journal of Pharmacology
Microglia represent the resident immune system in the brain. They mediate neuroinflammatory processes and have been described as important regulators of homeostasis in the central nervous system (CNS). Among several players and mechanisms contributing to microglial function in inflammation, ATP and glutamate have been shown to be involved in microgliosis. In this study, we focused on receptor subtypes that respond to these neurotransmitters, purinergic ionotropic P2X7 receptor and metabotropic glutamate mGlu₅ receptor. We found that both receptors are functionally expressed in a murine microglia cell line, BV2 cells, and we performed patch-clamp experiments to measure purinergic ionotropic P2X7 receptor ion flux in control condition and after metabotropic glutamate mGlu₅ receptor activation. The selective purinergic ionotropic P2X7 receptor agonist, 2′(3′)-O-(4-benzoylbenzoyl)adenosine-5′-triphosphate (BzATP, 100 μM), elicited a robust current that was prevented by the selective purinergic ionotropic P2X7 receptor antagonist A438079 (10 μM). When BV2 cells were acutely stimulated with the selective metabotropic glutamate mGlu₅ agonist, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG, 200 μM), purinergic ionotropic P2X7 receptor current was increased. This positive modulation was prevented by the selective metabotropic glutamate mGlu₅ receptor antagonist 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP, 1 μM). Moreover, nitric oxide synthesis elicited by purinergic ionotropic P2X7 receptor activation was enhanced by metabotropic glutamate mGlu₅ receptor co-stimulation. Taken together, our results suggest an important crosstalk between ATP and glutamate in inflammation. Pro-inflammatory effects mediated by purinergic ionotropic P2X7 receptor might be exacerbated by simultaneous exposure of microglia to ATP and glutamate, suggesting new pharmacological targets to modulate neuroinflammation.
Lithium-induced neuroprotective activity in neuronal and microglial cells: A purinergic perspective
2021, Psychiatry Research
Citation Excerpt :
Additionally, P2 × 7R has been reported as a crucial factor in microglial activation, inducing the production and release of inflammatory cytokines and leading to an inflammatory response (Suzuki, Hide et al. 2004, Bours, Swennen et al. 2006, Di Virgilio 2007). Speciffically, activation of P2 × 7R by extracellular ATP, promotes the processing and release of the cytokine interleukin-1β (IL-1β), inducing activation of microglia and macrophages associated with cell death (Brough, Le Feuvre et al. 2002). The concentrations of extracellular nucleotides (e.g. ATP, UTP) and nucleosides (adenosine) are controlled by ectonucleotidases such as members of the ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) family and ecto- 5’-nucleotidase/CD73 respectively (Robson, Sévigny et al. 2006).
Lithium is the mainstay of pharmacotherapy for treating bipolar disorder (BD). However, despite its wide use for over 60 years in the clinic, its mechanisms of action are not yet well defined. Elucidating lithium's mechanism of action will not only shed light on the pathophysiology of BD, but also potentially uncover new treatment targets. Previous studies suggest that the purinergic system may be involved in lithium's neuroprotective action; thus, the specific aim of this study is to better understand the neuroprotective action of lithium against ATP-induced cellular effect in both neuronal and microglial cellular lineages. We used PC12 neuronal and N9 microglial cells, evaluating cell death by cell counting and Annexin/PI cytometry assay, P2 × 7R immunocontent and ectonucleotidases activity, together with cytokine and nitrite assessment for microglial activity determination. Our results indicate that cells of different neural origins are responsive to ATP, in the sense of neuronal excitotoxicity and microglial switch into an activated M1-like phenotype respectively. Lithium, in turn, modulates the response in neuronal PC12 cells, preventing ATP-induced cell death. On the other hand, in N9 microglial cells, lithium was unable to prevent ATP-induced activation via P2 × 7R, indicating that lithium protective action against the effects of ATP more likely occurs in neurons rather than in microglia. Further studies are needed to better characterize the involvement of the purinergic system in the mechanism of action of lithium against neuronal death and microglial activation, in order to uncover new therapeutic adjunctive targets, such as antagonism of P2 × 7R, as potential approach for bipolar disorder treatment.
High intake of chicken and pork proteins aggravates high-fat-diet-induced inflammation and disorder of hippocampal glutamatergic system
2020, Journal of Nutritional Biochemistry
Citation Excerpt :
Astrocytes play a critical role in the central nervous system and in the pathogenesis of neurodegenerative diseases, which elicit a neuroprotective or deleterious effect when Tau protein and APP are highly expressed [36]. The β-amyloid could induce the activation of caspases and the death of astrocytes [37] by up-regulating SCNA and P2X7 [38,39]. However, no significant effect of the dietary protein type and level was observed on SCNA and P2X7 abundances, although Tau protein, APP and caspase exhibited significant differences among the diet groups, in particular between high- and low-protein diet groups.
High-fat diets have been associated with neurodegenerative diseases, which are also largely related to the type and amount of dietary proteins. However, to our knowledge, it is little known how dietary proteins affect neurodegenerative changes. In this study, we investigated the effects of dietary proteins in a high-fat diet on hippocampus functions related to enteric glial cells (EGCs) in Wistar rats that were fed either 40% or 20% (calorie) casein, chicken protein or pork protein for 12 weeks (n=10 each group). Inflammatory factors, glutamatergic system, EGCs, astrocytes and nutrient transporters were measured. A high-chicken-protein diet significantly increased the levels of systemic inflammatory factors, Tau protein and amyloid precursor protein mRNA level in the rat hippocampus. The type and level of dietary proteins in high-fat diets did not affect the gene expression of glial fibrillary acidic protein and α-synuclein (P>.05), indicating a negligible effect on astrocyte activity. However, the high-protein diets up-regulated glutamate transporters compared with the low-protein diets (P<.05), while they reduced the γ-aminobutyric acid content in high-chicken and -pork-protein diets (P<.05). Thus, compared with a low-protein diet (20%), a high-chicken or -pork-protein diet (40%) under a high-fat background could alter the balance between glutamatergic system and neurotransmitter and have a stronger effect on the interactions between hippocampal glutamatergic system and EGCs.
Advances in our understanding of gout as an auto-inflammatory disease
2020, Seminars in Arthritis and Rheumatism
Gout, the most common inflammatory arthritis, is the result of hyperuricemia and inflammation induced by monosodium urate (MSU) crystal deposition. However, most people with hyperuricemia will never develop gout, implying a molecular-genetic contribution to the development of gout. Recent genomic studies reveal links between certain genetic variations and gout. We highlight recent advances in our understanding of gout as an auto-inflammatory disease. We review the auto-inflammatory aspects of gout, including the inflammasome and thirteen gout-associated inflammatory-pathway genes and associated comorbidities. This information provides important insights into emerging immune-modulating targets in the management of gout, and future novel therapeutic targets in gout treatment. Cumulatively, this has important implications for treating gout as an auto-inflammatory disease, as opposed to a purely metabolic disease.

View all citing articles on Scopus

View full text

Regular ArticlePurinergic (P2X7) Receptor Activation of Microglia Induces Cell Death via an Interleukin-1-Independent Mechanism

Abstract

Immunol. Today

Blood

Neuropharmacology

Brain Res. Brain Res. Protocols

Brain Res. Mol. Brain Res.

Biochem. Biophys. Res. Commun.

Trends Neurosci.

J. Biol. Chem.

J. Neuroimmunol.

Neurosci. Lett.

J. Biol. Chem.

Brain Res. Brain Res. Rev.

Trends Neurosci.

Trends Neurosci.

J. Biol. Chem.

Int. J. Dev. Neurosci.

Effects of Escherichia coli hemolysin on human monocytes. Cytocidal action and stimulation of interleukin 1 release

J. Clin. Invest.

Evaluation of a tetrazolium-based semiautomated colorimetric assay: Assessment of chemosensitivity testing

Cancer Res.

Signal transduction via P2-purinergic receptors for extracellular ATP and other nucleotides

Am. J. Physiol.

Regular Article
Purinergic (P2X7) Receptor Activation of Microglia Induces Cell Death via an Interleukin-1-Independent Mechanism