Miltefosine increases macrophage cholesterol release and inhibits NLRP3-inflammasome assembly and IL-1β release
| العنوان: | Miltefosine increases macrophage cholesterol release and inhibits NLRP3-inflammasome assembly and IL-1β release |
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| المؤلفون: | Heather Andro, Jonathan D. Smith, Kailash Gulshan, Jennie E. Hazen, Harvey Lewis, Amanda J Iacano |
| المصدر: | Scientific Reports, Vol 9, Iss 1, Pp 1-12 (2019) Scientific Reports |
| بيانات النشر: | Springer Science and Business Media LLC, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| تدمد: | 2045-2322 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::92d24608f11b2a9324d5fe0734af0f01Test https://doi.org/10.1038/s41598-019-47610-wTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....92d24608f11b2a9324d5fe0734af0f01 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
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