Understanding the Mechanisms Controlling Leishmania amazonensis Infection In Vitro: The Role of LTB(4) Derived From Human Neutrophils

Neutrophils are rapidly recruited to the site of Leishmania infection and play an active role in capturing and killing parasites. They are the main source of leukotriene B(4) (LTB(4)), a potent proinflammatory lipid mediator. However, the role of LTB(4) in neutrophil infection by Leishmania amazonensis is not clear. In this study, we show that L. amazonensis or its lipophosphoglycan can induce neutrophil activation, degranulation, and LTB(4) production. Using pharmacological inhibitors of leukotriene synthesis, our findings reveal an LTB(4)-driven autocrine/paracrine regulatory effect. In particular, neutrophil-derived LTB(4) controls L. amazonensis killing, degranulation, and reactive oxygen species production. In addition, L. amazonensis infection induces an early increase in Toll-like receptor 2 expression, which facilitates parasite internalization. Nuclear factor kappa B (NFkB) pathway activation represents a required upstream event for L. amazonensis–induced LTB(4) synthesis. These leishmanicidal mechanisms mediated by neutrophil-derived LTB(4) act through activation of its receptor, B leukotriene receptor 1 (BLT1).