leukotriene-b4 and Leishmaniasis--Visceral

Eicosanoids and sand fly saliva have a critical role in the Leishmania infection. Here, we evaluated the effect of Lutzomyia longipalpis salivary gland sonicate (SGS) on neutrophil and monocyte recruitment and activation of eicosanoid production in a murine model of inflammation.. C57BL/6 mice were inoculated intraperitonealy with Lutzomyia longipalpis SGS or Leishmania infantum or both, followed by analyses of cell recruitment, parasite load and eicosanoid production.. Intraperitoneal injection of Lutzomyia longipalpis SGS together with Leishmania infantum induced an early increased parasite viability in monocytes and neutrophils. L. longipalpis SGS increased prostaglandin E2 (PGE2), but reduced leukotriene B4 (LTB4) production ex vivo in peritoneal leukocytes. In addition, the pharmacological inhibition of cyclooxygenase 2 (COX-2) with NS-398 decreased parasite viability inside macrophages during Leishmania infection in the presence of L. longipalpis SGS arguing that PGE2 production is associated with diminished parasite killing.. These findings indicate that L. longipalpis SGS is a critical factor driving immune evasion of Leishmania through modulation of PGE2/LTB4 axis, which may represent an important mechanism on establishment of the infection.

Topics: Animals; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Female; Humans; Leishmania infantum; Leishmaniasis, Visceral; Leukocytes; Leukotriene B4; Macrophages; Male; Mice; Mice, Inbred C57BL; Nitrobenzenes; Psychodidae; Salivary Glands; Sulfonamides

Macrophages act as the primary effector cells during Leishmania infection through production of reactive oxygen species (ROS) and interleukin-1β (IL-1β). However, how macrophage-killing mechanisms are activated during Leishmania-macrophage interactions is poorly understood. Here, we report that the macrophage response against Leishmania infantum in vivo is characterized by an M2b-like phenotype and C-type lectin receptors (CLRs) signature composed of Dectin-1, mannose receptor (MR), and the DC-SIGN homolog SIGNR3 expression. Dectin-1 and MR were crucial for the microbicidal response as indicated by the fact that they activated Syk-p47phox and arachidonic acid (AA)-NADPH oxidase signaling pathways, respectively, needed for ROS production and also triggered Syk-coupled signaling for caspase-1-induced IL-1β secretion. In contrast, SIGNR3 has divergent functions during Leishmania infantum pathogenesis; this CLR favored parasite resilience through inhibition of the LTB4-IL-1β axis. These pathways also operated during infection of primary human macrophages. Therefore, our study promotes CLRs as potential targets for treatment, diagnosis, and prevention of visceral leishmaniasis.

Topics: Animals; Antigens, CD; Arachidonic Acid; Caspase 1; Cells, Cultured; Humans; Interleukin-1beta; Intracellular Signaling Peptides and Proteins; Lectins, C-Type; Leishmania infantum; Leishmaniasis, Visceral; Leukotriene B4; Macrophages; Mannose Receptor; Mannose-Binding Lectins; Mice; Mice, Inbred C57BL; Mice, Knockout; NADPH Oxidases; Protein-Tyrosine Kinases; Reactive Oxygen Species; Receptors, Cell Surface; RNA Interference; RNA, Small Interfering; Signal Transduction; Syk Kinase