Abstract
Neutrophil extracellular traps (NETs) extruded from neutrophils upon activation are composed of chromatin associated with cytosolic and granular proteins, which ensnare and kill microorganisms. This microbicidal mechanism named classical netosis has been shown to dependent on reactive oxygen species (ROS) generation by NADPH oxidase and also chromatin decondensation dependent upon the enzymes (PAD4), neutrophil elastase (NE) and myeloperoxidase (MPO). NET release also occurs through an early/rapid ROS-independent mechanism, named early/rapid vital netosis. Here we analyze the role of ROS, NE, MPO and PAD4 in the netosis stimulated by Leishmania amazonensis promastigotes in human neutrophils. We demonstrate that promastigotes induce a classical netosis, dependent on the cellular redox imbalance, as well as by a chloroamidine sensitive and elastase activity mechanism. Additionally, Leishmania also induces the early/rapid NET release occurring only 10 minutes after neutrophil-parasite interaction. We demonstrate here, that this early/rapid mechanism is dependent on elastase activity, but independent of ROS generation and chloroamidine. A better understanding of both mechanisms of NET release, and the NETs effects on the host immune system modulation, could support the development of new potential therapeutic strategies for leishmaniasis.
Highlights
Neutrophils are the most abundant leukocytes in blood and play an important role in the innate immune response
We previously described that Leishmania amazonensis promastigotes induce Neutrophil extracellular traps (NETs) release from human neutrophils, are trapped by these scaffolds and killed by the histones associated to these structures[3]
We investigated the participation of elastase, myeloperoxidase and Peptidyl arginine deiminase 4 (PAD4) on NET formation induced in human neutrophils by L. amazonensis promastigotes
Summary
Neutrophils are the most abundant leukocytes in blood and play an important role in the innate immune response. We previously described that Leishmania amazonensis promastigotes induce NET release from human neutrophils, are trapped by these scaffolds and killed by the histones associated to these structures[3]. We investigated the participation of elastase, myeloperoxidase and PAD4 on NET formation induced in human neutrophils by L. amazonensis promastigotes. Our results demonstrate that Leishmania promastigotes trigger the classical netosis, by promoting redox imbalance, with the involvement of NADPH-oxidase and NOS derived ROS/RNS, respectively. This mechanism is dependent on PAD4 and elastase activity. Promastigotes promoted the early/rapid, ROS-independent NET formation occurring only 10 minutes after neutrophil-parasite interaction, which is dependent of elastase, but not on PAD4
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