Activated cholesterol metabolism is integral for innate macrophage responses by amplifying Myd88 signaling
Recent studies have shown that cellular metabolism is tightly linked to the regulation of immune cells. Here, we show that activation of cholesterol metabolism, involving cholesterol uptake, synthesis, and autophagy/lipophagy, is integral to innate immune responses in macrophages. In particular, cho...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2022-11-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.138539 |
| _version_ | 1797634360228184064 |
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| author | Sumio Hayakawa Atsushi Tamura Nikita Nikiforov Hiroyuki Koike Fujimi Kudo Yinglan Cheng Takuro Miyazaki Marina Kubekina Tatiana V. Kirichenko Alexander N. Orekhov Nobuhiko Yui Ichiro Manabe Yumiko Oishi |
| author_facet | Sumio Hayakawa Atsushi Tamura Nikita Nikiforov Hiroyuki Koike Fujimi Kudo Yinglan Cheng Takuro Miyazaki Marina Kubekina Tatiana V. Kirichenko Alexander N. Orekhov Nobuhiko Yui Ichiro Manabe Yumiko Oishi |
| author_sort | Sumio Hayakawa |
| collection | DOAJ |
| description | Recent studies have shown that cellular metabolism is tightly linked to the regulation of immune cells. Here, we show that activation of cholesterol metabolism, involving cholesterol uptake, synthesis, and autophagy/lipophagy, is integral to innate immune responses in macrophages. In particular, cholesterol accumulation within endosomes and lysosomes is a hallmark of the cellular cholesterol dynamics elicited by Toll-like receptor 4 activation and is required for amplification of myeloid differentiation primary response 88 (Myd88) signaling. Mechanistically, Myd88 binds cholesterol via its CLR recognition/interaction amino acid consensus domain, which promotes the protein’s self-oligomerization. Moreover, a novel supramolecular compound, polyrotaxane (PRX), inhibited Myd88‑dependent inflammatory macrophage activation by decreasing endolysosomal cholesterol via promotion of cholesterol trafficking and efflux. PRX activated liver X receptor, which led to upregulation of ATP binding cassette transporter A1, thereby promoting cholesterol efflux. PRX also inhibited atherogenesis in Ldlr–/– mice. In humans, cholesterol levels in circulating monocytes correlated positively with the severity of atherosclerosis. These findings demonstrate that dynamic changes in cholesterol metabolism are mechanistically linked to Myd88‑dependent inflammatory programs in macrophages and support the notion that cellular cholesterol metabolism is integral to innate activation of macrophages and is a potential therapeutic and diagnostic target for inflammatory diseases. |
| first_indexed | 2024-03-11T12:06:35Z |
| format | Article |
| id | doaj.art-5c9bc3d0a470412caf7bf83b653de058 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:35Z |
| publishDate | 2022-11-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-5c9bc3d0a470412caf7bf83b653de0582023-11-07T16:24:51ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-11-01722Activated cholesterol metabolism is integral for innate macrophage responses by amplifying Myd88 signalingSumio HayakawaAtsushi TamuraNikita NikiforovHiroyuki KoikeFujimi KudoYinglan ChengTakuro MiyazakiMarina KubekinaTatiana V. KirichenkoAlexander N. OrekhovNobuhiko YuiIchiro ManabeYumiko OishiRecent studies have shown that cellular metabolism is tightly linked to the regulation of immune cells. Here, we show that activation of cholesterol metabolism, involving cholesterol uptake, synthesis, and autophagy/lipophagy, is integral to innate immune responses in macrophages. In particular, cholesterol accumulation within endosomes and lysosomes is a hallmark of the cellular cholesterol dynamics elicited by Toll-like receptor 4 activation and is required for amplification of myeloid differentiation primary response 88 (Myd88) signaling. Mechanistically, Myd88 binds cholesterol via its CLR recognition/interaction amino acid consensus domain, which promotes the protein’s self-oligomerization. Moreover, a novel supramolecular compound, polyrotaxane (PRX), inhibited Myd88‑dependent inflammatory macrophage activation by decreasing endolysosomal cholesterol via promotion of cholesterol trafficking and efflux. PRX activated liver X receptor, which led to upregulation of ATP binding cassette transporter A1, thereby promoting cholesterol efflux. PRX also inhibited atherogenesis in Ldlr–/– mice. In humans, cholesterol levels in circulating monocytes correlated positively with the severity of atherosclerosis. These findings demonstrate that dynamic changes in cholesterol metabolism are mechanistically linked to Myd88‑dependent inflammatory programs in macrophages and support the notion that cellular cholesterol metabolism is integral to innate activation of macrophages and is a potential therapeutic and diagnostic target for inflammatory diseases.https://doi.org/10.1172/jci.insight.138539InflammationVascular biology |
| spellingShingle | Sumio Hayakawa Atsushi Tamura Nikita Nikiforov Hiroyuki Koike Fujimi Kudo Yinglan Cheng Takuro Miyazaki Marina Kubekina Tatiana V. Kirichenko Alexander N. Orekhov Nobuhiko Yui Ichiro Manabe Yumiko Oishi Activated cholesterol metabolism is integral for innate macrophage responses by amplifying Myd88 signaling JCI Insight Inflammation Vascular biology |
| title | Activated cholesterol metabolism is integral for innate macrophage responses by amplifying Myd88 signaling |
| title_full | Activated cholesterol metabolism is integral for innate macrophage responses by amplifying Myd88 signaling |
| title_fullStr | Activated cholesterol metabolism is integral for innate macrophage responses by amplifying Myd88 signaling |
| title_full_unstemmed | Activated cholesterol metabolism is integral for innate macrophage responses by amplifying Myd88 signaling |
| title_short | Activated cholesterol metabolism is integral for innate macrophage responses by amplifying Myd88 signaling |
| title_sort | activated cholesterol metabolism is integral for innate macrophage responses by amplifying myd88 signaling |
| topic | Inflammation Vascular biology |
| url | https://doi.org/10.1172/jci.insight.138539 |
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