| Autor: |
Thorstenberg ML; Laboratório de Imunofisiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Rangel Ferreira MV; Laboratório de Imunofisiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Amorim N; Laboratório de inflamação, Instituto de Biofísica Carlos Chagas Filho, Rio de Janeiro, Brazil., Canetti C; Laboratório de inflamação, Instituto de Biofísica Carlos Chagas Filho, Rio de Janeiro, Brazil., Morrone FB; Laboratório de Farmacologia Aplicada, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil., Alves Filho JC; Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil., Coutinho-Silva R; Laboratório de Imunofisiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. |
| Abstrakt: |
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 P2Y 2 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 B 4 (LTB 4 ) production in macrophages. UTP-induced parasite control was blocked by pharmacological antagonism of P2Y 2 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 P2Y 2 and P2X7 receptors cooperate to trigger potent innate immune responses against L. amazonensis infection. |
