Involvement of P2 receptors in hematopoiesis and hematopoietic disorders, and as pharmacological targets

Filippin, Kelly Juliana; Souza, Kamylla Fernanda Souza de; Júnior, Roberto T. Araujo; Torquato, Heron Fernandes Vieira; Dias, Dhébora Albuquerque; Parisotto, Eduardo Benedetti; Ferreira, Alice Teixeira; Paredes‐Gamero, Edgar Julian

doi:10.1007/s11302-019-09684-z

Cited by 20 publications

(17 citation statements)

References 187 publications

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“…G-CSF or AMD3100 induces the egress of HSPCs into the PB. The activation of innate immune cells (especially Gr-1 + leucocytes) in the BM microenvironment releases DAMPs, including ATP, proteolytic and lipolytic enzymes, HGMB-1, S100a9, and ROS [ 104 ].…”

Section: Extracellular Signals Activate the Inflammasome Through Pmentioning

confidence: 99%

Inflammasomes and the Maintenance of Hematopoietic Homeostasis: New Perspectives and Opportunities

Yang

et al. 2021

Molecules

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Hematopoietic stem cells (HSCs) regularly produce various blood cells throughout life via their self-renewal, proliferation, and differentiation abilities. Most HSCs remain quiescent in the bone marrow (BM) and respond in a timely manner to either physiological or pathological cues, but the underlying mechanisms remain to be further elucidated. In the past few years, accumulating evidence has highlighted an intermediate role of inflammasome activation in hematopoietic maintenance, post-hematopoietic transplantation complications, and senescence. As a cytosolic protein complex, the inflammasome participates in immune responses by generating a caspase cascade and inducing cytokine secretion. This process is generally triggered by signals from purinergic receptors that integrate extracellular stimuli such as the metabolic factor ATP via P2 receptors. Furthermore, targeted modulation/inhibition of specific inflammasomes may help to maintain/restore adequate hematopoietic homeostasis. In this review, we will first summarize the possible relationships between inflammasome activation and homeostasis based on certain interesting phenomena. The cellular and molecular mechanism by which purinergic receptors integrate extracellular cues to activate inflammasomes inside HSCs will then be described. We will also discuss the therapeutic potential of targeting inflammasomes and their components in some diseases through pharmacological or genetic strategies.

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Section: Extracellular Signals Activate the Inflammasome Through Pmentioning

confidence: 99%

Inflammasomes and the Maintenance of Hematopoietic Homeostasis: New Perspectives and Opportunities

Yang

et al. 2021

Molecules

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“…Extracellular adenine nucleotides and their breakdown product, adenosine, can trigger many different cell responses, including cell adhesion, migration, proliferation, differentiation and death in normal cells [ 10 , 14 , 15 , 16 ] and leukemic bone marrow cells [ 15 , 17 ]. ATP and ADP act by binding to the P2 receptor family, which is subdivided into two subgroups: P2X, a ligand-gated ion channel receptor (only for ATP), and P2Y, a G protein-coupled receptor (for ATP, ADP, UTP, UDP or UDP–glucose) [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Extracellular Adenine Nucleotides and Adenosine Modulate the Growth and Survival of THP-1 Leukemia Cells

Puchałowicz

Tarnowski

Tkacz

et al. 2020

IJMS

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A new approach to improve the effectiveness of acute myeloid leukemia (AML) treatment is to use the properties of purinergic signaling molecules secreted into the bone marrow milieu in response to leukemic cell growth. Therefore, our study aimed to evaluate the effects of extracellular adenine nucleotides and adenosine on the growth and death parameters in the leukemic THP-1 cell line. Cells were exposed to ATP, ADP, AMP, adenosine and nonhydrolyzable analogues of ATP and ADP (ATPγS and ADPβS) in a 1–1000 μM broad concentration range. The basal mRNA expression of the P1 and P2 receptors was evaluated by real-time PCR. Changes in the processes of cell growth and death were assessed by flow cytometry analysis of proliferation, cell cycle and apoptosis. Chemotaxis toward stromal cell-derived factor-1 (SDF-1) was performed using the modified Boyden chamber assay, and chemokine receptor type 4 (CXCR4) surface expression was quantified by flow cytometry. We indicated several antileukemic actions. High micromolar concentrations (100–1000 μM) of extracellular adenine nucleotides and adenosine inhibit the growth of cells by arresting the cell cycle and/or inducing apoptosis. ATP is characterized by the highest potency and widest range of effects, and is responsible for the cell cycle arrest and the apoptosis induction. Compared to ATP, the effect of ADP is slightly weaker. Adenosine mostly has a cytotoxic effect, with the induction of apoptosis. The last studied nucleotide, AMP, demonstrated only a weak cytotoxic effect without affecting the cell cycle. In addition, cell migration towards SDF-1 was inhibited by low micromolar concentrations (10 μM). One of the reasons for this action of ATPγS and adenosine was a reduction in CXCR4 surface expression, but this only partially explains the mechanism of antimigratory action. In summary, extracellular adenine nucleotides and adenosine inhibit THP-1 cell growth, cause death of cells and modulate the functioning of the SDF-1/CXCR4 axis. Thus, they negatively affect the processes that are responsible for the progression of AML and the difficulties in AML treatment.

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“…With regard to the cellular localization of P2X7R, P2X7R is initially found to be expressed in peripheral hematopoietic cells, lymphocytes, and macrophages [ 55 ]. Following in-depth research, it is believed that 67% of the P2X7R is also concentrated in the CNS and mainly expressed in glial cells in the CNS, especially microglia [ 56 , 57 ].…”

Section: Discussionmentioning

confidence: 99%

P2X7R-mediated autophagic impairment contributes to central sensitization in a chronic migraine model with recurrent nitroglycerin stimulation in mice

Jiang

Zhang

Feng

et al. 2021

J Neuroinflammation

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Background Central sensitization is an important pathophysiological mechanism of chronic migraine (CM). According to our previous studies, microglial activation and subsequent inflammation in the trigeminal nucleus caudalis (TNC) contribute to the central sensitization. The P2X7 receptor (P2X7R) is a purinergic receptor expressed in microglia and participates in central sensitization in chronic pain, but its role in CM is unclear. Numerous studies have shown that P2X7R regulates the level of autophagy and that autophagy affects the microglial activation and inflammation. Recently, autophagy has been shown to be involved in neuropathic pain, but there is no information about autophagy in CM. Therefore, the current study investigated the role of P2X7R in CM and its underlying mechanism, focusing on autophagy regulation. Methods The CM model was established by repeated intraperitoneal injection of nitroglycerin (NTG) in mice. A Von Frey filament and radiant heat were used to assess the mechanical and thermal hypersensitivity. Western blotting and immunofluorescence assays were performed to detect the expression of P2X7R, autophagy-related proteins, and the cellular localization of P2X7R. To determine the role of P2X7R and autophagy in CM, we detected the effects of the autophagy inducer, rapamycin (RAPA) and P2X7R antagonist, Brilliant Blue G (BBG), on pain behavior and the expression of calcitonin gene-related peptide (CGRP) and c-fos. In addition, the effect of RAPA and BBG on microglial activation and subsequent inflammation were investigated. Results The expression of P2X7R was increased and was mainly colocalized with microglia in the TNC following recurrent NTG administration. The autophagic flux was blocked in CM, which was characterized by upregulated LC3-II, and accumulated autophagy substrate protein, p62. RAPA significantly improved the basal rather than acute hyperalgesia. BBG alleviated both basal and acute hyperalgesia. BBG activated the level of autophagic flux. RAPA and BBG inhibited the activation of microglia, limited the inflammatory response, and reduced the expression of CGRP and c-fos. Conclusions Our results demonstrate the dysfunction of the autophagic process in CM. Activated autophagy may have a preventive effect on migraine chronification. P2X7R contributes to central sensitization through mediating autophagy regulation and might become a potential target for CM.

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Involvement of P2 receptors in hematopoiesis and hematopoietic disorders, and as pharmacological targets

Cited by 20 publications

References 187 publications

Inflammasomes and the Maintenance of Hematopoietic Homeostasis: New Perspectives and Opportunities

Inflammasomes and the Maintenance of Hematopoietic Homeostasis: New Perspectives and Opportunities

Extracellular Adenine Nucleotides and Adenosine Modulate the Growth and Survival of THP-1 Leukemia Cells

P2X7R-mediated autophagic impairment contributes to central sensitization in a chronic migraine model with recurrent nitroglycerin stimulation in mice

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