P2X7 Receptor Triggers Lysosomal Leakage Through Calcium Mobilization in a Mechanism Dependent on Pannexin-1 Hemichannels

Abstract

The P2X7 receptor is a critical purinergic receptor in immune cells. Its activation was associated with cathepsin release into macrophage cytosol, suggesting its involvement in lysosomal membrane permeabilization (LMP) and leakage. Nevertheless, the mechanisms by which P2X7 receptor activation induces LMP and leakage are unclear. This study investigated cellular mechanisms associated with endosomal and lysosomal leakage triggered by P2X7 receptor activation. We found that ATP at 500 μM and 5 mM (but not 50 μM) induced LMP in non-stimulated peritoneal macrophages. This effect was not observed in P2X7-deficient or A740003-pretreated macrophages. We found that the P2X7 receptor and pannexin-1 channels mediate calcium influx that might be important for activating specific ion channels (TRPM2 and two-pore channels) on the membranes of late endosomes and lysosomes leading to LMP leakage and consequent cathepsin release. These findings suggest the critical role of the P2X7 receptor in inflammatory and infectious diseases via lysosomal dysfunction.

Novel 2-(5-Arylthiophen-2-yl)-benzoazole Cyclometalated Iridium(III) dppz Complexes Exhibit Selective Phototoxicity in Cancer Cells by Lysosomal Damage and Oncosis

“…56−58 Rapidly dividing cancer cells are strongly dependent on effective lysosomal function, and dramatic changes in lysosomal volume, composition, and cellular distribution occur during cancer transformation and progression; these changes promote the invasive growth of tumors. 59 This makes cancer cells more sensitive to the impairment of lysosomes. Moreover, apoptosis-resistant cancer cells can still undergo lysosomal cell death.…”

“…Moreover, apoptosis-resistant cancer cells can still undergo lysosomal cell death. 59 Thus, the targeting of lysosomes and induction of lysosome-dependent cell death represent promising therapeutic strategies for cancer treatment. 56 , 60 − 62 From this point of view, the Ir complexes described in this study offer exciting potential, mainly because the disintegration of lysosomes and subsequent cellular effects can be triggered explicitly by light at the tumor site.…”

Cathepsin C from extracellular histone-induced M1 alveolar macrophages promotes NETosis during lung ischemia-reperfusion injury

“…Previous research has identified mast cells in the trachea and AMs in the alveoli as primary sources of CTSC [ 78 ]. Moreover, studies have indicated that several DAMPs including cholesterol crystals and ATP, could induce LMP in macrophages and lead to the release of lysosomal proteases [ 79 , 80 ]. In our study, we confirmed that extracellular histones, among these same DAMPs, induced LMP in AMs using various fluorescence staining methods.…”

Cx43 hemichannels and panx1 channels contribute to ethanol-induced astrocyte dysfunction and damage

“…This signal triggers reactive astrogliosis and recruits microglia and other peripheral immune cells, thereby increasing the susceptibility of neurons to damage [85]. Since Cx43 hemichannels and Panx1 channels facilitate the release of ATP in astrocytes [52,53], and considering that ATP activates these channels by increasing the influx of Ca 2+ via P2X7 receptors [86,87], we evaluated whether these receptors play a role in ethanolinduced channel activity. Blocking P2X7 receptors with 200 nM A740003 or 200 µM oxidized ATP (oATP) partially decreased ethanol-induced Etd uptake (Fig.…”