Miltefosine increases macrophage cholesterol release and inhibits NLRP3-inflammasome assembly and IL-1β release

Scientific Reports
Amanda J IacanoKailash Gulshan

Abstract

Miltefosine is an FDA approved oral drug for treating cutaneous and visceral leishmaniasis. Leishmania is a flagellated protozoa, which infects and differentiates in macrophages. Here, we studied the effects of Miltefosine on macrophage's lipid homeostasis, autophagy, and NLRP3 inflammasome assembly/activity. Miltefosine treatment conferred multiple effects on macrophage lipid homeostasis leading to increased cholesterol release from cells, increased lipid-raft disruption, decreased phosphatidylserine (PS) flip from the cell-surface, and redistribution of phosphatidylinositol 4,5-bisphosphate (PIP2) from the plasma membrane to actin rich regions in the cells. Enhanced basal autophagy, lipophagy and mitophagy was observed in cells treated with Miltefosine vs. control. Miltefosine treated cells showed marked increased in phosphorylation of kinases involved in autophagy induction such as; Adenosine monophosphate-activated protein kinase (AMPK) and Unc-51 like autophagy activating kinase (ULK1). The Toll like receptor (TLR) signaling pathway was blunted by Miltefosine treatment, resulting in decreased TLR4 recruitment to cell-surface and ~75% reduction in LPS induced pro-IL-1β mRNA levels. Miltefosine reduced endotoxin-mediated mit...Continue Reading

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Citations

Jun 22, 2020·Immunological Reviews·Valerie Harrington, Prajwal Gurung
Jul 8, 2020·International Journal of Molecular Sciences·Jae-Min YukEun-Kyeong Jo
May 16, 2020·Frontiers in Pharmacology·Ferda KaleağasıoğluMartin R Berger
Dec 17, 2020·Vaccines·Lu LuKelvin Kai-Wang To
May 23, 2021·The International Journal of Biochemistry & Cell Biology·Soumya Ranjan MishraSujit Kumar Bhutia
Aug 17, 2021·Frontiers in Cell and Developmental Biology·Emmanuel OpokuKailash Gulshan

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Methods Mentioned

BETA
flow cytometry
flow-cytometry
transfection

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