CD36/Lyn kinase interactions within macrophages promotes pulmonary fibrosis in response to oxidized phospholipid
Abstract 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 previ...
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| Format: | Article |
| Language: | English |
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BMC
2023-12-01
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| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12931-023-02629-6 |
| _version_ | 1797388120038047744 |
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| author | Doyun Kwak Patrick B. Bradley Natalia Subbotina Song Ling Seagal Teitz-Tennenbaum John J. Osterholzer Thomas H. Sisson Kevin K. Kim |
| author_facet | Doyun Kwak Patrick B. Bradley Natalia Subbotina Song Ling Seagal Teitz-Tennenbaum John J. Osterholzer Thomas H. Sisson Kevin K. Kim |
| author_sort | Doyun Kwak |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-08T22:36:15Z |
| format | Article |
| id | doaj.art-39e09de905044eec8437fa4e79f8ce7f |
| institution | Directory Open Access Journal |
| issn | 1465-993X |
| language | English |
| last_indexed | 2024-03-08T22:36:15Z |
| publishDate | 2023-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-39e09de905044eec8437fa4e79f8ce7f2023-12-17T12:27:44ZengBMCRespiratory Research1465-993X2023-12-0124111710.1186/s12931-023-02629-6CD36/Lyn kinase interactions within macrophages promotes pulmonary fibrosis in response to oxidized phospholipidDoyun Kwak0Patrick B. Bradley1Natalia Subbotina2Song Ling3Seagal Teitz-Tennenbaum4John J. Osterholzer5Thomas H. Sisson6Kevin K. Kim7Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of MichiganDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of MichiganDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of MichiganDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of MichiganDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of MichiganDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of MichiganDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of MichiganDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of MichiganAbstract 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.https://doi.org/10.1186/s12931-023-02629-6CD36Oxidized phospholipidPulmonary fibrosisMacrophageTGFβLyn kinase |
| spellingShingle | Doyun Kwak Patrick B. Bradley Natalia Subbotina Song Ling Seagal Teitz-Tennenbaum John J. Osterholzer Thomas H. Sisson Kevin K. Kim CD36/Lyn kinase interactions within macrophages promotes pulmonary fibrosis in response to oxidized phospholipid Respiratory Research CD36 Oxidized phospholipid Pulmonary fibrosis Macrophage TGFβ Lyn kinase |
| title | CD36/Lyn kinase interactions within macrophages promotes pulmonary fibrosis in response to oxidized phospholipid |
| title_full | CD36/Lyn kinase interactions within macrophages promotes pulmonary fibrosis in response to oxidized phospholipid |
| title_fullStr | CD36/Lyn kinase interactions within macrophages promotes pulmonary fibrosis in response to oxidized phospholipid |
| title_full_unstemmed | CD36/Lyn kinase interactions within macrophages promotes pulmonary fibrosis in response to oxidized phospholipid |
| title_short | CD36/Lyn kinase interactions within macrophages promotes pulmonary fibrosis in response to oxidized phospholipid |
| title_sort | cd36 lyn kinase interactions within macrophages promotes pulmonary fibrosis in response to oxidized phospholipid |
| topic | CD36 Oxidized phospholipid Pulmonary fibrosis Macrophage TGFβ Lyn kinase |
| url | https://doi.org/10.1186/s12931-023-02629-6 |
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