Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses
Abstract Atherosclerosis is a chronic inflammatory disease with high morbidity and mortality rates worldwide. Doublecortin‐like kinase 1 (DCLK1), a microtubule‐associated protein kinase, is involved in neurogenesis and human cancers. However, the role of DCLK1 in atherosclerosis remains undefined. I...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2023-03-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202217198 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849343189014544384 |
|---|---|
| author | Zhuqi Huang Sirui Shen Xue Han Weixin Li Wu Luo Liming Lin Mingjiang Xu Yi Wang Weijian Huang Gaojun Wu Guang Liang |
| author_facet | Zhuqi Huang Sirui Shen Xue Han Weixin Li Wu Luo Liming Lin Mingjiang Xu Yi Wang Weijian Huang Gaojun Wu Guang Liang |
| author_sort | Zhuqi Huang |
| collection | DOAJ |
| description | Abstract Atherosclerosis is a chronic inflammatory disease with high morbidity and mortality rates worldwide. Doublecortin‐like kinase 1 (DCLK1), a microtubule‐associated protein kinase, is involved in neurogenesis and human cancers. However, the role of DCLK1 in atherosclerosis remains undefined. In this study, we identified upregulated DCLK1 in macrophages in atherosclerotic lesions of ApoE−/− mice fed an HFD and determined that macrophage‐specific DCLK1 deletion attenuates atherosclerosis by reducing inflammation in mice. Mechanistically, RNA sequencing analysis indicated that DCLK1 mediates oxLDL‐induced inflammation via NF‐κB signaling pathway in primary macrophages. Coimmunoprecipitation followed by LC–MS/MS analysis identified IKKβ as a binding protein of DCLK1. We confirmed that DCLK1 directly interacts with IKKβ and phosphorylates IKKβ at S177/181, thereby facilitating subsequent NF‐κB activation and inflammatory gene expression in macrophages. Finally, a pharmacological inhibitor of DCLK1 prevents atherosclerotic progression and inflammation both in vitro and in vivo. Our findings demonstrated that macrophage DCLK1 promotes inflammatory atherosclerosis by binding to IKKβ and activating IKKβ/NF‐κB. This study reports DCLK1 as a new IKKβ regulator in inflammation and a potential therapeutic target for inflammatory atherosclerosis. |
| format | Article |
| id | doaj-art-77588e6d0d2c4f83a5fb111b485a11b3 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-77588e6d0d2c4f83a5fb111b485a11b32025-08-20T03:43:10ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-03-0115511510.15252/emmm.202217198Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responsesZhuqi Huang0Sirui Shen1Xue Han2Weixin Li3Wu Luo4Liming Lin5Mingjiang Xu6Yi Wang7Weijian Huang8Gaojun Wu9Guang Liang10Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Cardiology, The First Affiliated Hospital of Wenzhou Medical UniversityChemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical UniversityChemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical UniversityChemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical UniversityChemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical UniversityChemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical UniversityChemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical UniversityDepartment of Cardiology, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Cardiology, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Cardiology, The First Affiliated Hospital of Wenzhou Medical UniversityAbstract Atherosclerosis is a chronic inflammatory disease with high morbidity and mortality rates worldwide. Doublecortin‐like kinase 1 (DCLK1), a microtubule‐associated protein kinase, is involved in neurogenesis and human cancers. However, the role of DCLK1 in atherosclerosis remains undefined. In this study, we identified upregulated DCLK1 in macrophages in atherosclerotic lesions of ApoE−/− mice fed an HFD and determined that macrophage‐specific DCLK1 deletion attenuates atherosclerosis by reducing inflammation in mice. Mechanistically, RNA sequencing analysis indicated that DCLK1 mediates oxLDL‐induced inflammation via NF‐κB signaling pathway in primary macrophages. Coimmunoprecipitation followed by LC–MS/MS analysis identified IKKβ as a binding protein of DCLK1. We confirmed that DCLK1 directly interacts with IKKβ and phosphorylates IKKβ at S177/181, thereby facilitating subsequent NF‐κB activation and inflammatory gene expression in macrophages. Finally, a pharmacological inhibitor of DCLK1 prevents atherosclerotic progression and inflammation both in vitro and in vivo. Our findings demonstrated that macrophage DCLK1 promotes inflammatory atherosclerosis by binding to IKKβ and activating IKKβ/NF‐κB. This study reports DCLK1 as a new IKKβ regulator in inflammation and a potential therapeutic target for inflammatory atherosclerosis.https://doi.org/10.15252/emmm.202217198atherosclerosisDCLK1IKKβinflammationmacrophage |
| spellingShingle | Zhuqi Huang Sirui Shen Xue Han Weixin Li Wu Luo Liming Lin Mingjiang Xu Yi Wang Weijian Huang Gaojun Wu Guang Liang Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses EMBO Molecular Medicine atherosclerosis DCLK1 IKKβ inflammation macrophage |
| title | Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses |
| title_full | Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses |
| title_fullStr | Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses |
| title_full_unstemmed | Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses |
| title_short | Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses |
| title_sort | macrophage dclk1 promotes atherosclerosis via binding to ikkβ and inducing inflammatory responses |
| topic | atherosclerosis DCLK1 IKKβ inflammation macrophage |
| url | https://doi.org/10.15252/emmm.202217198 |
| work_keys_str_mv | AT zhuqihuang macrophagedclk1promotesatherosclerosisviabindingtoikkbandinducinginflammatoryresponses AT siruishen macrophagedclk1promotesatherosclerosisviabindingtoikkbandinducinginflammatoryresponses AT xuehan macrophagedclk1promotesatherosclerosisviabindingtoikkbandinducinginflammatoryresponses AT weixinli macrophagedclk1promotesatherosclerosisviabindingtoikkbandinducinginflammatoryresponses AT wuluo macrophagedclk1promotesatherosclerosisviabindingtoikkbandinducinginflammatoryresponses AT liminglin macrophagedclk1promotesatherosclerosisviabindingtoikkbandinducinginflammatoryresponses AT mingjiangxu macrophagedclk1promotesatherosclerosisviabindingtoikkbandinducinginflammatoryresponses AT yiwang macrophagedclk1promotesatherosclerosisviabindingtoikkbandinducinginflammatoryresponses AT weijianhuang macrophagedclk1promotesatherosclerosisviabindingtoikkbandinducinginflammatoryresponses AT gaojunwu macrophagedclk1promotesatherosclerosisviabindingtoikkbandinducinginflammatoryresponses AT guangliang macrophagedclk1promotesatherosclerosisviabindingtoikkbandinducinginflammatoryresponses |