CD36/Lyn kinase interactions within macrophages promotes pulmonary fibrosis in response to oxidized phospholipid
© 2023. The Author(s)..
Recent data from human studies and animal models have established roles for type II alveolar epithelial cell (AEC2) injury/apoptosis and monocyte/macrophage accumulation and activation in progressive lung fibrosis. Although the link between these processes is not well defined, we have previously shown that CD36-mediated uptake of apoptotic AEC2s by lung macrophages is sufficient to drive fibrosis. Importantly, apoptotic AEC2s are rich in oxidized phospholipids (oxPL), and amongst its multiple functions, CD36 serves as a scavenger receptor for oxPL. Recent studies have established a role for oxPLs in alveolar scarring, and we hypothesized that uptake and accrual of oxPL by CD36 would cause a macrophage phenotypic change that promotes fibrosis. To test this hypothesis, we treated wild-type and CD36-null mice with the oxPL derivative oxidized phosphocholine (POVPC) and found that CD36-null mice were protected from oxPL-induced scarring. Compared to WT mice, fewer macrophages accumulated in the lungs of CD36-null animals, and the macrophages exhibited a decreased accumulation of intracellular oxidized lipid. Importantly, the attenuated accrual of oxPL in CD36-null macrophages was associated with diminished expression of the profibrotic mediator, TGFβ. Finally, the pathway linking oxPL uptake and TGFβ expression was found to require CD36-mediated activation of Lyn kinase. Together, these observations elucidate a causal pathway that connects AEC2 injury with lung macrophage activation via CD36-mediated uptake of oxPL and suggest several potential therapeutic targets.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
Respiratory research - 24(2023), 1 vom: 14. Dez., Seite 314 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kwak, Doyun [VerfasserIn] |
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| Links: |
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| Themen: |
CD36 |
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| Anmerkungen: |
Date Completed 16.12.2023 Date Revised 25.04.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1186/s12931-023-02629-6 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM365887285 |
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| 520 | |a © 2023. The Author(s). | ||
| 520 | |a Recent data from human studies and animal models have established roles for type II alveolar epithelial cell (AEC2) injury/apoptosis and monocyte/macrophage accumulation and activation in progressive lung fibrosis. Although the link between these processes is not well defined, we have previously shown that CD36-mediated uptake of apoptotic AEC2s by lung macrophages is sufficient to drive fibrosis. Importantly, apoptotic AEC2s are rich in oxidized phospholipids (oxPL), and amongst its multiple functions, CD36 serves as a scavenger receptor for oxPL. Recent studies have established a role for oxPLs in alveolar scarring, and we hypothesized that uptake and accrual of oxPL by CD36 would cause a macrophage phenotypic change that promotes fibrosis. To test this hypothesis, we treated wild-type and CD36-null mice with the oxPL derivative oxidized phosphocholine (POVPC) and found that CD36-null mice were protected from oxPL-induced scarring. Compared to WT mice, fewer macrophages accumulated in the lungs of CD36-null animals, and the macrophages exhibited a decreased accumulation of intracellular oxidized lipid. Importantly, the attenuated accrual of oxPL in CD36-null macrophages was associated with diminished expression of the profibrotic mediator, TGFβ. Finally, the pathway linking oxPL uptake and TGFβ expression was found to require CD36-mediated activation of Lyn kinase. Together, these observations elucidate a causal pathway that connects AEC2 injury with lung macrophage activation via CD36-mediated uptake of oxPL and suggest several potential therapeutic targets | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Lyn kinase | |
| 650 | 4 | |a Macrophage | |
| 650 | 4 | |a Oxidized phospholipid | |
| 650 | 4 | |a Pulmonary fibrosis | |
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| 650 | 7 | |a Transforming Growth Factor beta |2 NLM | |
| 700 | 1 | |a Bradley, Patrick B |e verfasserin |4 aut | |
| 700 | 1 | |a Subbotina, Natalia |e verfasserin |4 aut | |
| 700 | 1 | |a Ling, Song |e verfasserin |4 aut | |
| 700 | 1 | |a Teitz-Tennenbaum, Seagal |e verfasserin |4 aut | |
| 700 | 1 | |a Osterholzer, John J |e verfasserin |4 aut | |
| 700 | 1 | |a Sisson, Thomas H |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Kevin K |e verfasserin |4 aut | |
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