P2X7 Receptor-Mediated Release of Cathepsins from Macrophages Is a Cytokine-Independent Mechanism Potentially Involved in Joint Diseases

López-Castejón, Gloria; Theaker, Jill; Pelegrı́n, Pablo; Clifton, Andrew D.; Braddock, Martin; Surprenant, Annmarie

doi:10.4049/jimmunol.1000436

Cited by 99 publications

(102 citation statements)

References 59 publications

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“…Rather, the results agree well with previous reports that show that cathepsin B is associated with maturation of IL-1b in the endolysosomal compartment (51) and that stimulation of P2X 7 R induces secretion of cathepsin B (50,52).…”

Section: Saa-induced Inflammasome Activation Is Dependent On Cathepsin Bsupporting

confidence: 93%

Serum Amyloid A Activates the NLRP3 Inflammasome via P2X7 Receptor and a Cathepsin B-Sensitive Pathway

Niemi

Teirilä

Lappalainen

et al. 2011

The Journal of Immunology

250

225

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Serum amyloid A (SAA) is an acute-phase protein, the serum levels of which can increase up to 1000-fold during inflammation. SAA has a pathogenic role in amyloid A-type amyloidosis, and increased serum levels of SAA correlate with the risk for cardiovascular diseases. IL-1β is a key proinflammatory cytokine, and its secretion is strictly controlled by the inflammasomes. We studied the role of SAA in the regulation of IL-1β production and activation of the inflammasome cascade in human and mouse macrophages, as well as in THP-1 cells. SAA could provide a signal for the induction of pro–IL-1β expression and for inflammasome activation, resulting in secretion of mature IL-1β. Blocking TLR2 and TLR4 attenuated SAA-induced expression of IL1B, whereas inhibition of caspase-1 and the ATP receptor P2X7 abrogated the release of mature IL-1β. NLRP3 inflammasome consists of the NLRP3 receptor and the adaptor protein apoptosis-associated speck-like protein containing CARD (a caspase-recruitment domain) (ASC). SAA-mediated IL-1β secretion was markedly reduced in ASC−/− macrophages, and silencing NLRP3 decreased IL-1β secretion, confirming NLRP3 as the SAA-responsive inflammasome. Inflammasome activation was dependent on cathepsin B activity, but it was not associated with lysosomal destabilization. SAA also induced secretion of cathepsin B and ASC. In conclusion, SAA can induce the expression of pro–IL-1β and activation of the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway. Thus, during systemic inflammation, SAA may promote the production of IL-1β in tissues. Furthermore, the SAA-induced secretion of active cathepsin B may lead to extracellular processing of SAA and, thus, potentially to the development of amyloid A amyloidosis.

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Section: Saa-induced Inflammasome Activation Is Dependent On Cathepsin Bsupporting

confidence: 93%

Serum Amyloid A Activates the NLRP3 Inflammasome via P2X7 Receptor and a Cathepsin B-Sensitive Pathway

Niemi

Teirilä

Lappalainen

et al. 2011

The Journal of Immunology

250

225

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“…Cathepsins were initially characterized as specific lysosomal markers, and the release of mature forms in the extracellular compartment was observed from epithelial cells (Rodriguez et al, 1997) as well as immune cells (Lopez-Castejon et al, 2010) and proposed to be mainly due to lysosomal exocytosis. These proteases are often upregulated in various human cancers including breast cancer and are implicated in numerous tumourigenic processes, such as invasion and metastasis (Mohamed and Sloane, 2006).…”

Section: Discussionmentioning

confidence: 99%

P2X7 receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness

et al. 2011

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ATP-gated P2X 7 receptors (P2X 7 R) are unusual plasma membrane ion channels that have been extensively studied in immune cells. More recently, P2X 7 R have been described as potential cancer cell biomarkers. However, mechanistic links between P2X 7 R and cancer cell processes are unknown. Here, we show, in the highly aggressive human breast cancer cell line MDA-MB-435s, that P2X 7 receptor is highly expressed and fully functional. Its activation is responsible for the extension of neurite-like cellular prolongations, of the increase in cell migration by 35% and in cell invasion through extracellular matrix by 150%. The change in cancer cell morphology and the increased migration appeared to be due to the activation of Ca 2 þ -activated SK3 potassium channels. The enhanced invasion through the extracellular matrix was related to the increase of mature forms of cysteine cathepsins in the extracellular medium, which was independent of SK3 channel activity and not associated with cell death. Pharmacological targeting of P2X 7 R in vivo was crucial for cell invasiveness in a zebrafish model of metastases. Our results demonstrate a novel mechanistic link between P2X 7 R functionality in cancer cells and invasiveness, a key parameter in tumour growth and in the development of metastases. They also suggest a potential therapeutic role for the newly developed P2X 7 R antagonists.

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“…Prolonged stimulation with ATP also leads to caspase-1 dependent, but IL-1β and IL-18 cytokine processing independent cell death in macrophages [87,98,99]. b P2X7 receptor activation has also been shown to signal caspase-1 and IL-1β/IL-18 independent release of cathepsins [111,112], PGE 2 [8], phosphatidylserine [113], and MMP-9 [114], all of which are implicated in cellular processes that play a defined role in inflammation. ATP is also reported to act as a long-range "find me" signal (chemoattractant) to recruit monocytes and macrophages [115].…”

Section: Macrophagesmentioning

confidence: 99%

“…Besides the caspase-1 dependent processes described above, P2X7 receptor activation has also been shown to signal caspase-1 and IL-1β/IL-18 independent release of cathepsins [111,112], prostaglandin (PG)E 2 [8], phosphatidylserine [113], and matrix metalloproteinase 9 [114], all of which are implicated in cellular processes that play a defined role in inflammation.…”

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

200

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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P2X7 Receptor-Mediated Release of Cathepsins from Macrophages Is a Cytokine-Independent Mechanism Potentially Involved in Joint Diseases

Abstract: Material

Cited by 99 publications

References 59 publications

Serum Amyloid A Activates the NLRP3 Inflammasome via P2X7 Receptor and a Cathepsin B-Sensitive Pathway

Serum Amyloid A Activates the NLRP3 Inflammasome via P2X7 Receptor and a Cathepsin B-Sensitive Pathway

P2X7 receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness

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

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