Laboratory of Molecular Biology and Biochemistry of Proteins, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Laboratory of Immuno-Biophysics, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Front Immunol. 2022 Feb 9;13:752105. doi: 10.3389/fimmu.2022.752105. eCollection 2022.
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 lysosomal dysfunction.
P2X7 受体是免疫细胞中一种重要的嘌呤能受体。其激活与组织蛋白酶向巨噬细胞质溶胶中的释放有关，提示其参与溶酶体膜通透性（LMP）和渗漏。然而，P2X7 受体激活诱导 LMP 和渗漏的机制尚不清楚。本研究探讨了 P2X7 受体激活引发的内体和溶酶体渗漏相关的细胞机制。我们发现，500 μM 和 5 mM 的 ATP（但不是 50 μM）可诱导非刺激性腹腔巨噬细胞发生 LMP。在缺乏 P2X7 受体或用 A740003 预处理的巨噬细胞中未观察到这种作用。我们发现，P2X7 受体和 Pannexin-1 通道介导钙内流，这对于激活晚期内体和溶酶体膜上的特定离子通道（TRPM2 和双孔通道）可能很重要，导致 LMP 渗漏和随后的组织蛋白酶释放。这些发现表明 P2X7 受体在炎症和感染性疾病中溶酶体功能障碍中起着关键作用。
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