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Miltefosine increases macrophage cholesterol release and inhibits NLRP3-inflammasome assembly and IL-1β release
- Source :
- Scientific Reports, Vol 9, Iss 1, Pp 1-12 (2019), Scientific Reports
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
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 mitochondrial reactive oxygen species and protected the mitochondrial membrane potential. Miltefosine treatment induced mitophagy and dampened NLRP3 inflammasome assembly. Collectively, our data shows that Miltefosine induced ABCA1 mediated cholesterol release, induced AMPK phosphorylation and mitophagy, while dampening NLRP3 inflammasome assembly and IL-1β release.Significance StatementAtherosclerosis is driven by cholesterol accumulation and inflammation, and the arterial macrophage is a key cell type in both of these processes. The macrophage characteristics that protect against atherosclerosis include increased cholesterol efflux/reverse cholesterol transport, increased autophagy, and deceased inflammatory cytokine production and signaling. Here, we show that one single orally available compound, Miltefosine, can target multiple macrophage pathways involved in lipid homeostasis and inflammation. Miltefosine activated cholesterol release and autophagy while inhibiting pro IL-1β gene expression and NLRP3 inflammasome assembly. Miltefosine activated AMPK signaling pathway and mitophagy, leading to reduced NLRP3 inflammasome assembly and IL-1β release.
- Subjects :
- 0301 basic medicine
Inflammasomes
Interleukin-1beta
lcsh:Medicine
030204 cardiovascular system & hematology
Mice
0302 clinical medicine
Mitophagy
Phosphorylation
lcsh:Science
0303 health sciences
Multidisciplinary
biology
Chemistry
Kinase
Reverse cholesterol transport
Inflammasome
Mitochondria
3. Good health
Cell biology
Cholesterol
medicine.symptom
Signal Transduction
medicine.drug
Phosphorylcholine
Immunology
Inflammation
Article
Cell Line
03 medical and health sciences
NLR Family, Pyrin Domain-Containing 3 Protein
Autophagy
medicine
Animals
Humans
Protein kinase A
030304 developmental biology
Miltefosine
Macrophages
lcsh:R
AMPK
HEK293 Cells
RAW 264.7 Cells
030104 developmental biology
ABCA1
biology.protein
lcsh:Q
Reactive Oxygen Species
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 20452322
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....92d24608f11b2a9324d5fe0734af0f01