Efferocytosis potentiates the expression of arachidonate 15-lipoxygenase (ALOX15) in alternatively activated human macrophages through LXR activation
Macrophages acquire anti-inflammatory and proresolving functions to facilitate resolution of inflammation and promote tissue repair. While alternatively activated macrophages (AAMs), also referred to as M2 macrophages, polarized by type 2 (Th2) cytokines IL-4 or IL-13 contribute to the suppression o...
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| Veröffentlicht in: | Cell death and differentiation 2021-04, Vol.28 (4), p.1301-1316 |
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| creator | Snodgrass, Ryan G. Benatzy, Yvonne Schmid, Tobias Namgaladze, Dmitry Mainka, Malwina Schebb, Nils Helge Lütjohann, Dieter Brüne, Bernhard |
| description | Macrophages acquire anti-inflammatory and proresolving functions to facilitate resolution of inflammation and promote tissue repair. While alternatively activated macrophages (AAMs), also referred to as M2 macrophages, polarized by type 2 (Th2) cytokines IL-4 or IL-13 contribute to the suppression of inflammatory responses and play a pivotal role in wound healing, contemporaneous exposure to apoptotic cells (ACs) potentiates the expression of anti-inflammatory and tissue repair genes. Given that liver X receptors (LXRs), which coordinate sterol metabolism and immune cell function, play an essential role in the clearance of ACs, we investigated whether LXR activation following engulfment of ACs selectively potentiates the expression of Th2 cytokine-dependent genes in primary human AAMs. We show that AC uptake simultaneously upregulates LXR-dependent, but suppresses SREBP-2-dependent gene expression in macrophages, which are both prevented by inhibiting Niemann–Pick C1 (NPC1)-mediated sterol transport from lysosomes. Concurrently, macrophages accumulate sterol biosynthetic intermediates desmosterol, lathosterol, lanosterol, and dihydrolanosterol but not cholesterol-derived oxysterols. Using global transcriptome analysis, we identify anti-inflammatory and proresolving genes including interleukin-1 receptor antagonist (IL1RN) and arachidonate 15-lipoxygenase (ALOX15) whose expression are selectively potentiated in macrophages upon concomitant exposure to ACs or LXR agonist T0901317 (T09) and Th2 cytokines. We show priming macrophages via LXR activation enhances the cellular capacity to synthesize inflammation-suppressing specialized proresolving mediator (SPM) precursors 15-HETE and 17-HDHA as well as resolvin D5. Silencing LXRα and LXRβ in macrophages attenuates the potentiation of ALOX15 expression by concomitant stimulation of ACs or T09 and IL-13. Collectively, we identify a previously unrecognized mechanism of regulation whereby LXR integrates AC uptake to selectively shape Th2-dependent gene expression in AAMs. |
| doi_str_mv | 10.1038/s41418-020-00652-4 |
| format | Article |
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While alternatively activated macrophages (AAMs), also referred to as M2 macrophages, polarized by type 2 (Th2) cytokines IL-4 or IL-13 contribute to the suppression of inflammatory responses and play a pivotal role in wound healing, contemporaneous exposure to apoptotic cells (ACs) potentiates the expression of anti-inflammatory and tissue repair genes. Given that liver X receptors (LXRs), which coordinate sterol metabolism and immune cell function, play an essential role in the clearance of ACs, we investigated whether LXR activation following engulfment of ACs selectively potentiates the expression of Th2 cytokine-dependent genes in primary human AAMs. We show that AC uptake simultaneously upregulates LXR-dependent, but suppresses SREBP-2-dependent gene expression in macrophages, which are both prevented by inhibiting Niemann–Pick C1 (NPC1)-mediated sterol transport from lysosomes. Concurrently, macrophages accumulate sterol biosynthetic intermediates desmosterol, lathosterol, lanosterol, and dihydrolanosterol but not cholesterol-derived oxysterols. Using global transcriptome analysis, we identify anti-inflammatory and proresolving genes including interleukin-1 receptor antagonist (IL1RN) and arachidonate 15-lipoxygenase (ALOX15) whose expression are selectively potentiated in macrophages upon concomitant exposure to ACs or LXR agonist T0901317 (T09) and Th2 cytokines. We show priming macrophages via LXR activation enhances the cellular capacity to synthesize inflammation-suppressing specialized proresolving mediator (SPM) precursors 15-HETE and 17-HDHA as well as resolvin D5. Silencing LXRα and LXRβ in macrophages attenuates the potentiation of ALOX15 expression by concomitant stimulation of ACs or T09 and IL-13. Collectively, we identify a previously unrecognized mechanism of regulation whereby LXR integrates AC uptake to selectively shape Th2-dependent gene expression in AAMs.</description><identifier>ISSN: 1350-9047</identifier><identifier>EISSN: 1476-5403</identifier><identifier>DOI: 10.1038/s41418-020-00652-4</identifier><identifier>PMID: 33177619</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/106 ; 13/109 ; 13/2 ; 13/31 ; 13/89 ; 38/39 ; 38/91 ; 631/250/1933 ; 631/250/256/2515 ; 631/45/287/1197 ; 82/58 ; 82/80 ; Apoptosis ; Arachidonate 15-lipoxygenase ; Arachidonate 15-Lipoxygenase - genetics ; Arachidonate 15-Lipoxygenase - metabolism ; Biochemistry ; Biomedical and Life Sciences ; Cell activation ; Cell Biology ; Cell Cycle Analysis ; Cholesterol ; Cholesterol - metabolism ; Cytokines ; Cytokines - genetics ; Cytokines - metabolism ; Fluorocarbons - pharmacology ; Gene Expression ; Gene Expression Profiling ; Humans ; Immune clearance ; Inflammation ; Interleukin 1 ; Interleukin 1 receptor antagonist ; Interleukin 13 ; Interleukin 4 ; Intermediates ; Lanosterol ; Life Sciences ; Lipid Metabolism ; Lipoxygenase ; Liver X receptors ; Lymphocytes T ; Lysosomes ; Macrophages ; Macrophages - immunology ; Macrophages - metabolism ; Npc1 protein ; Phagocytosis ; Protein Binding ; Receptor mechanisms ; RNA, Small Interfering - genetics ; Stem Cells ; Sterol regulatory element-binding protein ; Sterols ; Sulfonamides - pharmacology ; Transcriptomes ; Wound healing</subject><ispartof>Cell death and differentiation, 2021-04, Vol.28 (4), p.1301-1316</ispartof><rights>The Author(s) 2020</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-816ec342a8a21a4df55baf2ed115ffa5d22bd856dfdafa330216a5f301ccd0153</citedby><cites>FETCH-LOGICAL-c474t-816ec342a8a21a4df55baf2ed115ffa5d22bd856dfdafa330216a5f301ccd0153</cites><orcidid>0000-0001-8237-2841</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027700/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027700/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,41488,42557,51319,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33177619$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Snodgrass, Ryan G.</creatorcontrib><creatorcontrib>Benatzy, Yvonne</creatorcontrib><creatorcontrib>Schmid, Tobias</creatorcontrib><creatorcontrib>Namgaladze, Dmitry</creatorcontrib><creatorcontrib>Mainka, Malwina</creatorcontrib><creatorcontrib>Schebb, Nils Helge</creatorcontrib><creatorcontrib>Lütjohann, Dieter</creatorcontrib><creatorcontrib>Brüne, Bernhard</creatorcontrib><title>Efferocytosis potentiates the expression of arachidonate 15-lipoxygenase (ALOX15) in alternatively activated human macrophages through LXR activation</title><title>Cell death and differentiation</title><addtitle>Cell Death Differ</addtitle><addtitle>Cell Death Differ</addtitle><description>Macrophages acquire anti-inflammatory and proresolving functions to facilitate resolution of inflammation and promote tissue repair. While alternatively activated macrophages (AAMs), also referred to as M2 macrophages, polarized by type 2 (Th2) cytokines IL-4 or IL-13 contribute to the suppression of inflammatory responses and play a pivotal role in wound healing, contemporaneous exposure to apoptotic cells (ACs) potentiates the expression of anti-inflammatory and tissue repair genes. Given that liver X receptors (LXRs), which coordinate sterol metabolism and immune cell function, play an essential role in the clearance of ACs, we investigated whether LXR activation following engulfment of ACs selectively potentiates the expression of Th2 cytokine-dependent genes in primary human AAMs. We show that AC uptake simultaneously upregulates LXR-dependent, but suppresses SREBP-2-dependent gene expression in macrophages, which are both prevented by inhibiting Niemann–Pick C1 (NPC1)-mediated sterol transport from lysosomes. Concurrently, macrophages accumulate sterol biosynthetic intermediates desmosterol, lathosterol, lanosterol, and dihydrolanosterol but not cholesterol-derived oxysterols. Using global transcriptome analysis, we identify anti-inflammatory and proresolving genes including interleukin-1 receptor antagonist (IL1RN) and arachidonate 15-lipoxygenase (ALOX15) whose expression are selectively potentiated in macrophages upon concomitant exposure to ACs or LXR agonist T0901317 (T09) and Th2 cytokines. We show priming macrophages via LXR activation enhances the cellular capacity to synthesize inflammation-suppressing specialized proresolving mediator (SPM) precursors 15-HETE and 17-HDHA as well as resolvin D5. Silencing LXRα and LXRβ in macrophages attenuates the potentiation of ALOX15 expression by concomitant stimulation of ACs or T09 and IL-13. Collectively, we identify a previously unrecognized mechanism of regulation whereby LXR integrates AC uptake to selectively shape Th2-dependent gene expression in AAMs.</description><subject>13</subject><subject>13/106</subject><subject>13/109</subject><subject>13/2</subject><subject>13/31</subject><subject>13/89</subject><subject>38/39</subject><subject>38/91</subject><subject>631/250/1933</subject><subject>631/250/256/2515</subject><subject>631/45/287/1197</subject><subject>82/58</subject><subject>82/80</subject><subject>Apoptosis</subject><subject>Arachidonate 15-lipoxygenase</subject><subject>Arachidonate 15-Lipoxygenase - genetics</subject><subject>Arachidonate 15-Lipoxygenase - metabolism</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Cell activation</subject><subject>Cell Biology</subject><subject>Cell Cycle Analysis</subject><subject>Cholesterol</subject><subject>Cholesterol - metabolism</subject><subject>Cytokines</subject><subject>Cytokines - genetics</subject><subject>Cytokines - metabolism</subject><subject>Fluorocarbons - pharmacology</subject><subject>Gene Expression</subject><subject>Gene Expression Profiling</subject><subject>Humans</subject><subject>Immune clearance</subject><subject>Inflammation</subject><subject>Interleukin 1</subject><subject>Interleukin 1 receptor antagonist</subject><subject>Interleukin 13</subject><subject>Interleukin 4</subject><subject>Intermediates</subject><subject>Lanosterol</subject><subject>Life Sciences</subject><subject>Lipid Metabolism</subject><subject>Lipoxygenase</subject><subject>Liver X receptors</subject><subject>Lymphocytes T</subject><subject>Lysosomes</subject><subject>Macrophages</subject><subject>Macrophages - immunology</subject><subject>Macrophages - metabolism</subject><subject>Npc1 protein</subject><subject>Phagocytosis</subject><subject>Protein Binding</subject><subject>Receptor mechanisms</subject><subject>RNA, Small Interfering - genetics</subject><subject>Stem Cells</subject><subject>Sterol regulatory element-binding protein</subject><subject>Sterols</subject><subject>Sulfonamides - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death and differentiation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Snodgrass, Ryan G.</au><au>Benatzy, Yvonne</au><au>Schmid, Tobias</au><au>Namgaladze, Dmitry</au><au>Mainka, Malwina</au><au>Schebb, Nils Helge</au><au>Lütjohann, Dieter</au><au>Brüne, Bernhard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Efferocytosis potentiates the expression of arachidonate 15-lipoxygenase (ALOX15) in alternatively activated human macrophages through LXR activation</atitle><jtitle>Cell death and differentiation</jtitle><stitle>Cell Death Differ</stitle><addtitle>Cell Death Differ</addtitle><date>2021-04-01</date><risdate>2021</risdate><volume>28</volume><issue>4</issue><spage>1301</spage><epage>1316</epage><pages>1301-1316</pages><issn>1350-9047</issn><eissn>1476-5403</eissn><abstract>Macrophages acquire anti-inflammatory and proresolving functions to facilitate resolution of inflammation and promote tissue repair. While alternatively activated macrophages (AAMs), also referred to as M2 macrophages, polarized by type 2 (Th2) cytokines IL-4 or IL-13 contribute to the suppression of inflammatory responses and play a pivotal role in wound healing, contemporaneous exposure to apoptotic cells (ACs) potentiates the expression of anti-inflammatory and tissue repair genes. Given that liver X receptors (LXRs), which coordinate sterol metabolism and immune cell function, play an essential role in the clearance of ACs, we investigated whether LXR activation following engulfment of ACs selectively potentiates the expression of Th2 cytokine-dependent genes in primary human AAMs. We show that AC uptake simultaneously upregulates LXR-dependent, but suppresses SREBP-2-dependent gene expression in macrophages, which are both prevented by inhibiting Niemann–Pick C1 (NPC1)-mediated sterol transport from lysosomes. Concurrently, macrophages accumulate sterol biosynthetic intermediates desmosterol, lathosterol, lanosterol, and dihydrolanosterol but not cholesterol-derived oxysterols. Using global transcriptome analysis, we identify anti-inflammatory and proresolving genes including interleukin-1 receptor antagonist (IL1RN) and arachidonate 15-lipoxygenase (ALOX15) whose expression are selectively potentiated in macrophages upon concomitant exposure to ACs or LXR agonist T0901317 (T09) and Th2 cytokines. We show priming macrophages via LXR activation enhances the cellular capacity to synthesize inflammation-suppressing specialized proresolving mediator (SPM) precursors 15-HETE and 17-HDHA as well as resolvin D5. Silencing LXRα and LXRβ in macrophages attenuates the potentiation of ALOX15 expression by concomitant stimulation of ACs or T09 and IL-13. Collectively, we identify a previously unrecognized mechanism of regulation whereby LXR integrates AC uptake to selectively shape Th2-dependent gene expression in AAMs.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33177619</pmid><doi>10.1038/s41418-020-00652-4</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0001-8237-2841</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Cell death and differentiation, 2021-04, Vol.28 (4), p.1301-1316 |
| issn | 1350-9047 1476-5403 |
| language | eng |
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| source | MEDLINE; SpringerLink Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | 13 13/106 13/109 13/2 13/31 13/89 38/39 38/91 631/250/1933 631/250/256/2515 631/45/287/1197 82/58 82/80 Apoptosis Arachidonate 15-lipoxygenase Arachidonate 15-Lipoxygenase - genetics Arachidonate 15-Lipoxygenase - metabolism Biochemistry Biomedical and Life Sciences Cell activation Cell Biology Cell Cycle Analysis Cholesterol Cholesterol - metabolism Cytokines Cytokines - genetics Cytokines - metabolism Fluorocarbons - pharmacology Gene Expression Gene Expression Profiling Humans Immune clearance Inflammation Interleukin 1 Interleukin 1 receptor antagonist Interleukin 13 Interleukin 4 Intermediates Lanosterol Life Sciences Lipid Metabolism Lipoxygenase Liver X receptors Lymphocytes T Lysosomes Macrophages Macrophages - immunology Macrophages - metabolism Npc1 protein Phagocytosis Protein Binding Receptor mechanisms RNA, Small Interfering - genetics Stem Cells Sterol regulatory element-binding protein Sterols Sulfonamides - pharmacology Transcriptomes Wound healing |
| title | Efferocytosis potentiates the expression of arachidonate 15-lipoxygenase (ALOX15) in alternatively activated human macrophages through LXR activation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-04T12%3A04%3A10IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Efferocytosis%20potentiates%20the%20expression%20of%20arachidonate%2015-lipoxygenase%20(ALOX15)%20in%20alternatively%20activated%20human%20macrophages%20through%20LXR%20activation&rft.jtitle=Cell%20death%20and%20differentiation&rft.au=Snodgrass,%20Ryan%20G.&rft.date=2021-04-01&rft.volume=28&rft.issue=4&rft.spage=1301&rft.epage=1316&rft.pages=1301-1316&rft.issn=1350-9047&rft.eissn=1476-5403&rft_id=info:doi/10.1038/s41418-020-00652-4&rft_dat=%3Cproquest_pubme%3E2460086121%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2509428228&rft_id=info:pmid/33177619&rfr_iscdi=true |