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.