Regulation of P2X7-dependent inflammatory functions by P2X4 receptor in mouse macrophages

Kawano, Atsushi; Tsukimoto, Mitsutoshi; Mori, Daisuke; Noguchi, Taisei; Hishida, Hitoshi; Takenouchi, Takato; Kitani, Hiroshi; Kojima, Shuji

doi:10.1016/j.bbrc.2012.02.122

Cited by 78 publications

(56 citation statements)

References 39 publications

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“…P2X7-induced ROS formation has been previously observed in myeloid cells [6][7][8][9][10][11][12]35], glomerular mesangial cells [36] and submandibular gland cells [30,31], but to the best of our knowledge, the current study is the first to demonstrate that P2X7 activation causes ROS formation in erythroid cells. It will be of future importance to determine if P2X7 induces ROS formation in primary erythroid cells.…”

Section: Discussionmentioning

confidence: 46%

“…The various biological roles attributed to P2X7 are the result of various signalling events downstream of P2X7 activation including reactive oxygen species (ROS) formation [5]. P2X7 activation induces ROS generation in a variety of cell types resulting in transcription factor activation [6], pro-inflammatory cytokine release [7,8], microbial killing [9], cell death [10,11] and autophagy [12]. However, it remains unknown if P2X7 activation can induce ROS formation in erythroid cells.…”

Section: Introductionmentioning

confidence: 99%

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P2X7 receptor activation induces reactive oxygen species formation in erythroid cells

Wang

Sluyter

2012

Purinergic Signalling

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The presence of P2X7 on erythroid cells is well established, but its physiological role remains unclear. The current study aimed to determine if P2X7 activation induces reactive oxygen species (ROS) formation in murine erythroleukaemia (MEL) cells, a commonly used erythroid cell line. ATP induced ROS formation in a time-and concentrationdependent fashion. The most potent P2X7 agonist, 2′(3′)-O-(4-benzoylbenzoyl)ATP, but not UTP or ADP, also induced ROS formation. The P2X7 antagonist, A-438079, impaired ATP-induced ROS formation. The ROS scavenger, N-acetyl-L-cysteine, and the ROS inhibitor, diphenyleneiodonium, also impaired P2X7-induced ROS formation, but use of enzymespecific ROS inhibitors failed to identify the intracellular source of P2X7-induced ROS formation. P2X7-induced ROS formation was impaired partly by physiological concentrations of Ca 2+ and Mg 2+ and almost completely in cells in N-methyl-D-glucamine chloride medium. The p38 MAPK inhibitors SB202190 and SB203580, and the caspase inhibitor Z-VAD-FMK, but not N-acetyl-L-cysteine, impaired P2X7-induced MEL cell apoptosis. ATP also stimulated p38 MAPK and caspase activation, both of which could be impaired by A-438079. In conclusion, these findings indicate that P2X7 activation induces ROS formation in MEL cells and that this process may be involved in events downstream of P2X7 activation, other than apoptosis, in erythroid cells.

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Section: Discussionmentioning

confidence: 46%

Section: Introductionmentioning

confidence: 99%

P2X7 receptor activation induces reactive oxygen species formation in erythroid cells

Wang

Sluyter

2012

Purinergic Signalling

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“…7, E and F, i-ii and iv-v), whereas a decrease was observed in livers of mice that contained the deletion of the P2X7 receptor gene (Fig. 7, E and F, iii and vi) (16,19). Results also indicated that P2X7 gene-deleted mice from both DIOϩBDCM-coexposed group had decreased amounts of HMGB-1 protein, a damageassociated molecular pattern linked to inflammation, as analyzed by Western blot (Fig.…”

Section: P2x7 Receptor Modulates Autophagy-linked Inflammation In Nashmentioning

confidence: 80%

Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis

Das

Seth

Kumar

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Das S, Seth RK, Kumar A, Kadiiska MB, Michelotti G, Diehl AM, Chatterjee S. Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 305: G950 -G963, 2013. First published October 24, 2013 doi:10.1152/ajpgi.00235.2013.-Recent studies indicate that metabolic oxidative stress, autophagy, and inflammation are hallmarks of nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanisms that link these important events in NASH remain unclear. In this study, we investigated the mechanistic role of purinergic receptor X7 (P2X7) in modulating autophagy and resultant inflammation in NASH in response to metabolic oxidative stress. The study uses two rodent models of NASH. In one of them, a CYP2E1 substrate bromodichloromethane is used to induce metabolic oxidative stress and NASH. Methyl choline-deficient diet feeding is used for the other NASH model. CYP2E1 and P2X7 receptor gene-deleted mice are used to establish their roles in regulating metabolic oxidative stress and autophagy. Autophagy gene expression, protein levels, confocal microscopy based-immunolocalization of lysosome-associated membrane protein (LAMP)2A and histopathological analysis were performed. CYP2E1-dependent metabolic oxidative stress induced increases in P2X7 receptor expression and chaperone-mediated autophagy markers LAMP2A and heat shock cognate 70 but caused depletion of light chain 3 isoform B (LC3B) protein levels. P2X7 receptor gene deletion significantly decreased LAMP2A and inflammatory indicators while significantly increasing LC3B protein levels compared with wild-type mice treated with bromodichloromethane. P2X7 receptor-deleted mice were also protected from NASH pathology as evidenced by decreased inflammation and fibrosis. Our studies establish that P2X7 receptor is a key regulator of autophagy induced by metabolic oxidative stress in NASH, thereby modulating hepatic inflammation. Furthermore, our findings presented here form a basis for P2X7 receptor as a potential therapeutic target in the treatment for NASH.5,5-dimethyl-1-pyrroline N-oxide-nitrone adducts; lipid peroxidation; tyrosine nitration; cytokines; CYP2E1; light chain 3 isoform B; GABA-A receptor-associated protein NONALCOHOLIC STEATOHEPATITIS (NASH) is associated with metabolic oxidative stress, often ascribed to enhanced oxidation of membrane lipids, mitochondrial uncoupling of the electron transport chain, and higher cytochrome P450 enzyme activity (18,29,30). Metabolic oxidative stress leads to cellular stress and induces cell death mechanisms, which modulate inflammatory microenvironment in NASH (5, 24).Cell death mechanisms in disease pathogenesis are synonymous with necrosis, autophagy, and apoptosis; however, much attention is recently focused on the various roles of autophagy in cellular processes, inflammation, energy homeostasis, and immunity (8, 35). Despite increased attention on autophagy, the mechanisms tha...

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“…However the host macrophages have developed a purinergic-mediated mechanism to counteract the escape efforts of these pathogens such as Mycobacterium [102], Vibrio cholerae [103], Pseudomonas aeruginosa [104], and Chlamydia trachomatis [105]; P2X7 receptor ligation can stimulate the inflammasome associated with secretion of cytokines but it can also lead to the direct killing of intracellular pathogens in infected macrophages, involving macrophage cell death and potentially related to macrophage autophagy [106,107]. The co-expression of P2X4 receptors with P2X7 receptors was subsequently found to suppress P2X7-mediated autophagy and to facilitate the release of pro-inflammatory mediators in mouse macrophage RAW264.7 cells, consequently enhancing inflammation [108]. This association of P2X4 with P2X7 was also described in relation to macrophage cell death [109] but for which the underlying molecular mechanism is not yet unveiled.…”

Section: Macrophagesmentioning

confidence: 99%

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

Jacob

Novo

Bachert

et al. 2013

Purinergic Signalling

197

158

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Extracellular ATP and related nucleotides promote a wide range of pathophysiological responses via activation of cell surface purinergic P2 receptors. Almost every cell type expresses P2 receptors and/or exhibit regulated release of ATP. In this review, we focus on the purinergic receptor distribution in inflammatory cells and their implication in diverse immune responses by providing an overview of the current knowledge in the literature related to purinergic signaling in neutrophils, macrophages, dendritic cells, lymphocytes, eosinophils, and mast cells. The pathophysiological role of purinergic signaling in these cells include among others calcium mobilization, actin polymerization, chemotaxis, release of mediators, cell maturation, cytotoxicity, and cell death. We finally discuss the therapeutic potential of P2 receptor subtype selective drugs in inflammatory conditions.

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Regulation of P2X7-dependent inflammatory functions by P2X4 receptor in mouse macrophages

Cited by 78 publications

References 39 publications

P2X7 receptor activation induces reactive oxygen species formation in erythroid cells

P2X7 receptor activation induces reactive oxygen species formation in erythroid cells

Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis

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

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