Abstract
Leishmania and other parasites display several mechanisms to subvert host immune cell function in order to achieve successful infection. The ATP receptor P2X7, an agonist-gated cation channel widely expressed in macrophages and other cells of the immune system, is also coupled to inflammasome activation, IL-1 beta secretion, production of reactive oxygen species, cell death and the induction of the permeabilization of the plasma membrane to molecules of up to 900 Da. P2X7 receptors can function as an effective microbicidal triggering receptor in macrophages infected with several microorganisms including Mycobacteria tuberculosis, Chlamydia and Leishmania. We have previously shown that its expression is up-regulated in macrophages infected with L.amazonensis and that infected cells also display an increase in P2X7-induced apoptosis and membrane permeabilization to some anionic fluorescent dyes. In an independent study we recently showed that the phenomenon of macrophage membrane permeabilization can involve at least two distinct pathways for cations and anions respectively. Here, we re-addressed the effects of ATP-induced P2X7-associated phenomena in macrophages infected with L.amazonensis and demonstrated that the P2X7-associated dye uptake mechanisms are differentially modulated. While the membrane permeabilization for anionic dyes is up-modulated, as previously described, the uptake of cationic dyes is strongly down-modulated. These results unveil new characteristics of two distinct permeabilization mechanisms associated with P2X7 receptors in macrophages and provide the first evidence indicating that these pathways can be differentially modulated in an immunologically relevant situation. The possible importance of these results to the L.amazonensis escape mechanism is discussed.
Highlights
Macrophages display strong differentiation plasticity characterized by the modulation of the expression of several membrane receptors, cytokine production, and functions such as migration, phagocytosis, microorganism killing and antigen presentation [1]
We have recently shown that L.amazonensis infection up-regulates P2X7 expression and renders the cells more susceptible to ATPe-induced apoptosis and we have shown that even at sub-lytic doses, ATPe can induce parasite elimination by macrophages [33]
Infected macrophages with morphological alterations characteristic of apoptosis - condensed nuclei, decreased cytosolic area/volume, loss of cytosolic electron density, and difficult to identify organelles - were clearly observed after ATP treatment (Fig. 2C) as well as cells displaying typical characteristics of necrosis such as loss of shape, shrinkage, and loss of plasma membrane structure (Fig. 2D), characteristics not present in untreated cells (Figs. 2A–B)
Summary
Macrophages display strong differentiation plasticity characterized by the modulation of the expression of several membrane receptors, cytokine production, and functions such as migration, phagocytosis, microorganism killing and antigen presentation [1]. These cells are the host of a number of intracellular pathogens such as Mycobacterium tuberculosis, Leishmania, Trypanosoma cruzi, and HIV-1 [2,3,4,5,6,7,8,9,10,11,12]. P2X7 receptors have been implied in cell death, inflammasome activation, secretion of IL1b, modulation of regulatory T cell function, and in the killing of intracellular microorganisms, among other effects [21,25,26,27,28,29,30]
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