Systemically Silencing Long Non-coding RNAs Maclpil With Short Interfering RNA Nanoparticles Alleviates Experimental Ischemic Stroke by Promoting Macrophage Apoptosis and Anti-inflammatory Activation
BackgroundMaclpil is a proinflammatory long non-coding RNA highly expressed on monocyte-derived macrophages in the ischemic brain. This study investigated the impact and the mechanisms of systemically delivering nanoparticle Maclpil short interfering RNA (siRNA) on experimental ischemic stroke in a...
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| Format: | Article |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2022.876087/full |
| _version_ | 1828350873495928832 |
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| author | Yan Wang Yan Wang Cuiying Liu Yong Chen Yong Chen Tiffany Chen Tao Han Lixiang Xue Lixiang Xue Baohui Xu |
| author_facet | Yan Wang Yan Wang Cuiying Liu Yong Chen Yong Chen Tiffany Chen Tao Han Lixiang Xue Lixiang Xue Baohui Xu |
| author_sort | Yan Wang |
| collection | DOAJ |
| description | BackgroundMaclpil is a proinflammatory long non-coding RNA highly expressed on monocyte-derived macrophages in the ischemic brain. This study investigated the impact and the mechanisms of systemically delivering nanoparticle Maclpil short interfering RNA (siRNA) on experimental ischemic stroke in a mouse model.MethodsIschemic stroke (focal cerebral ischemia) was induced in male C57BL/6 mice through the middle cerebral artery occlusion. Three hours thereafter, mice were intravenously injected with Maclpil siRNA or scramble siRNA nanoparticles. Bone marrow cell-derived macrophages were transfected with Maclpil or scramble siRNA and subjected to oxygen glucose deprivation culture. The influence of silencing Maclpil on stroke outcomes, neuroinflammation, and macrophage fates was assessed via histology, flow cytometry, Western blotting, and quantitative PCR analysis.ResultsThree days following stroke induction, siRNA silencing Maclpil substantially reduced ischemic infarction size and improved neurological behaviors. Silencing Maclpil also markedly attenuated the accumulation of monocyte-derived macrophages, CD4+ T cells, and CD8+ T cells in the ischemic hemisphere without affecting microglia cellularity. Reciprocally, myeloid cells and both subsets of T cells were elevated in mouse peripheral blood following Maclpil siRNA treatment. Under oxygen glucose deprivation conditions that mimicked hypoxia and hypoglycemia in vitro, Maclpil siRNA silencing augmented macrophage apoptosis in conjunction with upregulation of proapoptotic Bax and caspase 3 expressions. siRNA knocking down Maclpil skewed macrophages from proinflammatory classical toward anti-inflammatory alternative activation as evidenced by increased arginase 1, Ym1, and Fizz1 and reduced inducible nitric oxide synthase, IL-1β, and TNF-α mRNA levels. Consistent with macrophage phenotype switching, silencing Maclpil by siRNA enhanced fatty acid oxidation as indicated by increased mRNA levels of 3 key metabolic enzymes (ACADM, ACADVL, and HADHA).ConclusionSystemically silencing Maclpil by siRNA nanoparticles attenuated experimental ischemic stroke by promoting macrophage apoptosis and anti-inflammatory alternative activation. Identifying and targeting Maclpil human homolog(s) may help develop a novel therapy for stroke clinical management. |
| first_indexed | 2024-04-14T01:32:18Z |
| format | Article |
| id | doaj.art-d5408e3b36a044d8a8787826ceb25b1a |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-04-14T01:32:18Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-d5408e3b36a044d8a8787826ceb25b1a2022-12-22T02:20:09ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2022-05-01910.3389/fcvm.2022.876087876087Systemically Silencing Long Non-coding RNAs Maclpil With Short Interfering RNA Nanoparticles Alleviates Experimental Ischemic Stroke by Promoting Macrophage Apoptosis and Anti-inflammatory ActivationYan Wang0Yan Wang1Cuiying Liu2Yong Chen3Yong Chen4Tiffany Chen5Tao Han6Lixiang Xue7Lixiang Xue8Baohui Xu9Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, ChinaMedical Research Center, Peking University Third Hospital, Beijing, ChinaSchool of Nursing, Capital Medical University, Beijing, ChinaInstitute of Medical Innovation and Research, Peking University Third Hospital, Beijing, ChinaDepartment of Neurology, Peking University Third Hospital, Beijing, ChinaDepartment of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA, United StatesInstitute of Medical Innovation and Research, Peking University Third Hospital, Beijing, ChinaInstitute of Medical Innovation and Research, Peking University Third Hospital, Beijing, ChinaMedical Research Center, Peking University Third Hospital, Beijing, ChinaDepartment of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA, United StatesBackgroundMaclpil is a proinflammatory long non-coding RNA highly expressed on monocyte-derived macrophages in the ischemic brain. This study investigated the impact and the mechanisms of systemically delivering nanoparticle Maclpil short interfering RNA (siRNA) on experimental ischemic stroke in a mouse model.MethodsIschemic stroke (focal cerebral ischemia) was induced in male C57BL/6 mice through the middle cerebral artery occlusion. Three hours thereafter, mice were intravenously injected with Maclpil siRNA or scramble siRNA nanoparticles. Bone marrow cell-derived macrophages were transfected with Maclpil or scramble siRNA and subjected to oxygen glucose deprivation culture. The influence of silencing Maclpil on stroke outcomes, neuroinflammation, and macrophage fates was assessed via histology, flow cytometry, Western blotting, and quantitative PCR analysis.ResultsThree days following stroke induction, siRNA silencing Maclpil substantially reduced ischemic infarction size and improved neurological behaviors. Silencing Maclpil also markedly attenuated the accumulation of monocyte-derived macrophages, CD4+ T cells, and CD8+ T cells in the ischemic hemisphere without affecting microglia cellularity. Reciprocally, myeloid cells and both subsets of T cells were elevated in mouse peripheral blood following Maclpil siRNA treatment. Under oxygen glucose deprivation conditions that mimicked hypoxia and hypoglycemia in vitro, Maclpil siRNA silencing augmented macrophage apoptosis in conjunction with upregulation of proapoptotic Bax and caspase 3 expressions. siRNA knocking down Maclpil skewed macrophages from proinflammatory classical toward anti-inflammatory alternative activation as evidenced by increased arginase 1, Ym1, and Fizz1 and reduced inducible nitric oxide synthase, IL-1β, and TNF-α mRNA levels. Consistent with macrophage phenotype switching, silencing Maclpil by siRNA enhanced fatty acid oxidation as indicated by increased mRNA levels of 3 key metabolic enzymes (ACADM, ACADVL, and HADHA).ConclusionSystemically silencing Maclpil by siRNA nanoparticles attenuated experimental ischemic stroke by promoting macrophage apoptosis and anti-inflammatory alternative activation. Identifying and targeting Maclpil human homolog(s) may help develop a novel therapy for stroke clinical management.https://www.frontiersin.org/articles/10.3389/fcvm.2022.876087/fullischemic strokeneuroinflammationmacrophageslncRNA maclpilSiRNA nanoparticles |
| spellingShingle | Yan Wang Yan Wang Cuiying Liu Yong Chen Yong Chen Tiffany Chen Tao Han Lixiang Xue Lixiang Xue Baohui Xu Systemically Silencing Long Non-coding RNAs Maclpil With Short Interfering RNA Nanoparticles Alleviates Experimental Ischemic Stroke by Promoting Macrophage Apoptosis and Anti-inflammatory Activation Frontiers in Cardiovascular Medicine ischemic stroke neuroinflammation macrophages lncRNA maclpil SiRNA nanoparticles |
| title | Systemically Silencing Long Non-coding RNAs Maclpil With Short Interfering RNA Nanoparticles Alleviates Experimental Ischemic Stroke by Promoting Macrophage Apoptosis and Anti-inflammatory Activation |
| title_full | Systemically Silencing Long Non-coding RNAs Maclpil With Short Interfering RNA Nanoparticles Alleviates Experimental Ischemic Stroke by Promoting Macrophage Apoptosis and Anti-inflammatory Activation |
| title_fullStr | Systemically Silencing Long Non-coding RNAs Maclpil With Short Interfering RNA Nanoparticles Alleviates Experimental Ischemic Stroke by Promoting Macrophage Apoptosis and Anti-inflammatory Activation |
| title_full_unstemmed | Systemically Silencing Long Non-coding RNAs Maclpil With Short Interfering RNA Nanoparticles Alleviates Experimental Ischemic Stroke by Promoting Macrophage Apoptosis and Anti-inflammatory Activation |
| title_short | Systemically Silencing Long Non-coding RNAs Maclpil With Short Interfering RNA Nanoparticles Alleviates Experimental Ischemic Stroke by Promoting Macrophage Apoptosis and Anti-inflammatory Activation |
| title_sort | systemically silencing long non coding rnas maclpil with short interfering rna nanoparticles alleviates experimental ischemic stroke by promoting macrophage apoptosis and anti inflammatory activation |
| topic | ischemic stroke neuroinflammation macrophages lncRNA maclpil SiRNA nanoparticles |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2022.876087/full |
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