Abstract
The release of damage-associated molecular patterns, including uridine triphosphate (UTP) and adenosine triphosphate (ATP) to the extracellular milieu is a key component of innate immune response to infection. Previously, we showed that macrophage infection by the protozoan parasite Leishmania amazonensis—the etiological agent of cutaneous leishmaniasis—can be controlled by ATP- and UTP-mediated activation of P2Y and P2X7 receptors (activated by UTP/ATP and ATP, respectively), which provided comparable immune responses against the parasite. Interestingly, in context of Leishmania amazonensis infection, UTP/P2Y triggered apoptosis, reactive oxygen species, and oxide nitric (NO) production, which are characteristic of P2X7 receptor activation. Here, we examined a possible “cross-talk” between P2Y2 and P2X7 receptors, and the requirement for pannexin-1 (PANX-1) in the control of L. amazonensis infection in mouse peritoneal macrophages and in vivo. UTP treatment reduced L. amazonensis parasite load, induced extracellular ATP release [which was pannexin-1 (PANX-1) dependent], and triggered leukotriene B4 (LTB4) production in macrophages. UTP-induced parasite control was blocked by pharmacological antagonism of P2Y2 or P2X7 receptors and was absent in macrophages lacking P2X7 or PANX-1. In addition, ATP release induced by UTP was also inhibited by PANX-1 blocker carbenoxolone, and partially reversed by inhibitors of vesicle traffic and actin cytoskeleton dynamics. In vivo, UTP treatment reduced footpad and popliteal lymph node parasite load, and the lesion in wild-type (WT) mice; fact not observed in P2X7−/− mice. Our data reveal that P2Y2 and P2X7 receptors cooperate to trigger potent innate immune responses against L. amazonensis infection.
Highlights
According to the World Health Organization, leishmaniasis is the second most prevalent cause of parasite-associated deaths, being responsible for an estimated 30,000 deaths annually [1]
Assuming that different P2 receptors are upregulated in macrophages infected with L. amazonensis, we evaluated the “cross-talk” between P2 receptors of high and low affinity to adenosine triphosphate (ATP), as well P2Y2, and P2X7 receptors, both in vitro and in vivo, using knockout mouse models and pharmacological tolls
These results suggest that the ATP release triggered by eUTP in macrophages infected with L. amazonensis depends primarily on PANX-1 activity, and on an intact actin cytoskeleton
Summary
According to the World Health Organization, leishmaniasis is the second most prevalent cause of parasite-associated deaths, being responsible for an estimated 30,000 deaths annually [1]. We showed that Leishmania amazonensis infection positively modulates the expression of P2X7, P2Y2, and P2Y4 receptors in macrophages [19, 20], and that the activation of P2 receptors by nucleotide secretion is likely to represent a physiological mechanism for parasitism control [5], since UTP and ATP have crucial roles in restraining the proliferation of L. amazonensis [19, 20, 27]. P2Y activation by eUTP in L. amazonensis infected macrophages triggered effects traditionally associated with ATPmediated P2X7 activation, such as the apoptosis, NO, and ROS production, in a calcium-dependent manner [19]. These data suggest the existence of a “cross-talk” between ATP- and UTPmediated responses during Leishmania infection. Our data reveal the existence of a system whereby eUTP/ATP stimulation amplifies ATP secretion by infected macrophages—via the activation of PANX-1 channels—culminating in further P2X7 receptor ligation, generating LTB4, which boosts the immune response against L. amazonensis
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