ATP-Induced Killing of Mycobacteria by Human Macrophages Is Mediated by Purinergic P2Z(P2X7) Receptors

Abstract

The death of BCG-infected human macrophages induced in vitro by ligation of surface CD95 (Fas), CD69, or complement-mediated lysis was shown not to result in the death of intracellular mycobacteria, whereas exposure to extracellular ATP initiated both macrophage death and killed the intracellular bacteria. ATP acted via P2Z receptors because these effects were mimicked by benzoylbenzoic ATP (a known agonist of P2Z receptors) and blocked by oxidized ATP, DIDS, suramin, amiloride, and KN62 (known inhibitors of P2Z-mediated responses). ATP-mediated bacterial killing was independent of reactive nitrogen and oxygen intermediates and of actinomycin D or cycloheximide inhibition. ATP-induced macrophage cell death, BCG killing, and lucifer yellow dye incorporation were minimal in 2 out of 19 healthy donors. The results suggest possible genetic heterogeneity of this mechanism of mycobacterial killing associated with P2Z-mediated pore formation.

Dynamic regulation of the P2X4 receptor in alveolar macrophages by phagocytosis and classical activation

“…Classical activation of macrophages is intimately linked to induction of microbicidal activity and several studies have shown that P2X 7 R play a role in killing of Mycobacterium tuberculosis via activation of phospholipase D [8,9,35]. The down-regulation of surface P2X 4 R in classically activated alveolar macrophages makes it unlikely that P2X 4 R are involved in the killing of bacteria.…”

“…The case for P2X 7 R is now well established: Stimulation of P2X 7 R in activated monocytes, macrophages and microglia leads to rapid release of pro-inflammatory IL-1b and IL-18 cytokines, to phospholipase D activation and, if stimulation is sustained, to apopotosis [1,[3][4][5]. Classical activation of macrophages, generally induced by IFN-g and/or LPS, up-regulates P2X 7 R mRNA and protein levels and functional expression [6,7] and this correlates well with a role for P2X 7 R in bacterial killing [8,9]. Recently, highly selective and potent P2X 7 R antagonists have been identified [10] with one of these showing initial positive results in Phase II clinical trials for rheumatoid arthritis [11].…”

P2X7 receptors regulate multiple types of membrane trafficking responses and non-classical secretion pathways

“…P2X7R activation has been shown to promote the killing of both mycobacteria [50,57,58] and Chlamydia [59,60] in two ways: enhanced maturation of the microbe-containing phagosomes and enhanced killing of the microbe-infected host cells. The first mechanism involves a P2X7R-mediated activation of phospholipase D that facilitates maturation and fusion of the mycobacteria/ chlamydia-containing phagosomes with lysosomes [50].…”

Lipid metabolism modulation by the P2X7 receptor in the immune system and during the course of infection: new insights into the old view

“…Purinergic P2X receptors, especially P2X7R, are broadly distributed throughout immune cell types, such as, lymphocytes, monocytes, macrophages, neutrophils, eosinophils, and dendritic cells [71]. P2X7R plays an important role in various physiological processes in the immune system, some of which include killing pathogens [34,50,72,73], production of reactive oxygen and nitrogen species [74], maturation and release of pro-inflammatory cytokines [17][18][19]75], caspase activation [19,75], T cell maturation [76], pore-formation activity [77], and activation of phospholipases [34,50,51,72,78].…”