Liposomal cholesterol delivery activates the macrophage innate immune arm to facilitate intracellular Leishmania donovani killing.
Leishmania donovani causes visceral leishmaniasis (VL) by infecting the monocyte/macrophage lineage and residing inside specialized structures known as parasitophorous vacuoles. The protozoan parasite has adopted several means of escaping the host immune response, with one of the major methods being deactivation of host macrophages. Previous reports highlight dampened macrophage signaling, defective antigen presentation due to increased membrane fluidity, and the downregulation of several genes associated with L. donovani infection. We have reported previously that the defective antigen presentation in infected hamsters could be corrected by a single injection of a cholesterol-containing liposome. Here we show that cholesterol in the form of a liposomal formulation can stimulate the innate immune arm and reactivate macrophage function. Augmented levels of reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI), along with proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), corroborate intracellular parasite killing. Cholesterol incorporation kinetics is favored in infected macrophages more than in normal macrophages. Such an enhanced cholesterol uptake is associated with preferential apoptosis of infected macrophages in an endoplasmic reticulum (ER) stress-dependent manner. All these events are coupled with mitogen-activated protein (MAP) kinase activation, while inhibition of such pathways resulted in increased parasite loads. Hence, liposomal cholesterol is a potential facilitator of the macrophage effector function in favor of the host, independently of the T-cell arm.
Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India.
June
J
Ghosh
Rajan
R
Guha
Shantanabha
S
Das
Syamal
S
Roy
D000818:Animals; D002470:Cell Survival; D002784:Cholesterol / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D007155:Immunologic Factors / Q000378:metabolism*; D007893:Leishmania donovani / Q000276:immunology*; D008081:Liposomes / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology*; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D016207:Cytokines; D007155:Immunologic Factors; D008081:Liposomes; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D002784:Cholesterol