Miltefosine increases macrophage cholesterol release and inhibits NLRP3-inflammasome assembly and IL-1β release
Identifieur interne : 000867 ( Ncbi/Merge ); précédent : 000866; suivant : 000868Miltefosine increases macrophage cholesterol release and inhibits NLRP3-inflammasome assembly and IL-1β release
Auteurs : Amanda J. Iacano [États-Unis] ; Harvey Lewis [États-Unis] ; Jennie E. Hazen [États-Unis] ; Heather Andro [États-Unis] ; Jonathan D. Smith [États-Unis] ; Kailash Gulshan [États-Unis]Source :
- Scientific Reports [ 2045-2322 ] ; 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.
Url:
DOI: 10.1038/s41598-019-47610-w
PubMed: 31366948
PubMed Central: 6668382
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<front><div type="abstract" xml:lang="en"><p id="Par1">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.</p>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Sci Rep</journal-id>
<journal-id journal-id-type="iso-abbrev">Sci Rep</journal-id>
<journal-title-group><journal-title>Scientific Reports</journal-title>
</journal-title-group>
<issn pub-type="epub">2045-2322</issn>
<publisher><publisher-name>Nature Publishing Group UK</publisher-name>
<publisher-loc>London</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31366948</article-id>
<article-id pub-id-type="pmc">6668382</article-id>
<article-id pub-id-type="publisher-id">47610</article-id>
<article-id pub-id-type="doi">10.1038/s41598-019-47610-w</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Miltefosine increases macrophage cholesterol release and inhibits NLRP3-inflammasome assembly and IL-1β release</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Iacano</surname>
<given-names>Amanda J.</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lewis</surname>
<given-names>Harvey</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hazen</surname>
<given-names>Jennie E.</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Andro</surname>
<given-names>Heather</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Smith</surname>
<given-names>Jonathan D.</given-names>
</name>
<address><email>smithj4@ccf.org</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Gulshan</surname>
<given-names>Kailash</given-names>
</name>
<address><email>gulshak@ccf.org</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<aff id="Aff1"><label>1</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0675 4725</institution-id>
<institution-id institution-id-type="GRID">grid.239578.2</institution-id>
<institution>Department of Cardiovascular and Metabolic Sciences,</institution>
<institution>Cleveland Clinic,</institution>
</institution-wrap>
Cleveland, OH 44195 USA</aff>
<aff id="Aff2"><label>2</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0675 4725</institution-id>
<institution-id institution-id-type="GRID">grid.239578.2</institution-id>
<institution>Department of Cardiovascular Medicine,</institution>
<institution>Cleveland Clinic,</institution>
</institution-wrap>
Cleveland, OH 44195 USA</aff>
</contrib-group>
<pub-date pub-type="epub"><day>31</day>
<month>7</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>31</day>
<month>7</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><year>2019</year>
</pub-date>
<volume>9</volume>
<elocation-id>11128</elocation-id>
<history><date date-type="received"><day>6</day>
<month>2</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>18</day>
<month>6</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© The Author(s) 2019</copyright-statement>
<license license-type="OpenAccess"><license-p><bold>Open Access</bold>
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
.</license-p>
</license>
</permissions>
<abstract id="Abs1"><p id="Par1">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.</p>
</abstract>
<kwd-group kwd-group-type="npg-subject"><title>Subject terms</title>
<kwd>Cell biology</kwd>
<kwd>Immunology</kwd>
</kwd-group>
<funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/100000050</institution-id>
<institution>U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)</institution>
</institution-wrap>
</funding-source>
<award-id>R01 HL128268</award-id>
<award-id>R01 HL130085</award-id>
<principal-award-recipient><name><surname>Smith</surname>
<given-names>Jonathan D.</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/100000968</institution-id>
<institution>American Heart Association (American Heart Association, Inc.)</institution>
</institution-wrap>
</funding-source>
<award-id>SDG25710128</award-id>
<principal-award-recipient><name><surname>Gulshan</surname>
<given-names>Kailash</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s) 2019</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Ohio</li>
</region>
</list>
<tree><country name="États-Unis"><region name="Ohio"><name sortKey="Iacano, Amanda J" sort="Iacano, Amanda J" uniqKey="Iacano A" first="Amanda J." last="Iacano">Amanda J. Iacano</name>
</region>
<name sortKey="Andro, Heather" sort="Andro, Heather" uniqKey="Andro H" first="Heather" last="Andro">Heather Andro</name>
<name sortKey="Gulshan, Kailash" sort="Gulshan, Kailash" uniqKey="Gulshan K" first="Kailash" last="Gulshan">Kailash Gulshan</name>
<name sortKey="Hazen, Jennie E" sort="Hazen, Jennie E" uniqKey="Hazen J" first="Jennie E." last="Hazen">Jennie E. Hazen</name>
<name sortKey="Lewis, Harvey" sort="Lewis, Harvey" uniqKey="Lewis H" first="Harvey" last="Lewis">Harvey Lewis</name>
<name sortKey="Smith, Jonathan D" sort="Smith, Jonathan D" uniqKey="Smith J" first="Jonathan D." last="Smith">Jonathan D. Smith</name>
<name sortKey="Smith, Jonathan D" sort="Smith, Jonathan D" uniqKey="Smith J" first="Jonathan D." last="Smith">Jonathan D. Smith</name>
</country>
</tree>
</affiliations>
</record>
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