Sun-Hee Cho, Byeongkwon Choi, Jisun Lee, Yu-Sun Lee, Mi-Ock Baek, You-Jeung Lee, Chae-Ok Gil, Min-Kyung Choi, Sana Abdul Khaliq, Syeda Maham, Jae-Kyung Hyun, Gahyun Roh, Huijeong Choi, Sowon Lee, Seo-Hyeon Bae, Seonghyun Lee, Hyo-Jung Park, Jae-Hun Ahn, Na-Young Lee, Byeong-Cheol Kang, Young Kyo Seo, Byung-Kwan Lim, Jae-Hwan Nam, Mina Rho, Mee-Sup Yoon
{"title":"ApoE缺乏可保护代谢应激下注射部位mRNA疫苗诱导的线粒体功能障碍。","authors":"Sun-Hee Cho, Byeongkwon Choi, Jisun Lee, Yu-Sun Lee, Mi-Ock Baek, You-Jeung Lee, Chae-Ok Gil, Min-Kyung Choi, Sana Abdul Khaliq, Syeda Maham, Jae-Kyung Hyun, Gahyun Roh, Huijeong Choi, Sowon Lee, Seo-Hyeon Bae, Seonghyun Lee, Hyo-Jung Park, Jae-Hun Ahn, Na-Young Lee, Byeong-Cheol Kang, Young Kyo Seo, Byung-Kwan Lim, Jae-Hwan Nam, Mina Rho, Mee-Sup Yoon","doi":"10.7150/thno.119545","DOIUrl":null,"url":null,"abstract":"<p><p><b>Rationale:</b> The local tissue effects of mRNA vaccination remain incompletely understood. We investigated how SARS-CoV-2 mRNA vaccination impacts injection site tissues in the context of different metabolic states and apolipoprotein E (ApoE) status. <b>Methods:</b> We administered intramuscular SARS-CoV-2 mRNA vaccination to wild-type and ApoE-deficient mice under regular and high-fat diets, as well as macaques. We performed transcriptomic analysis, ultrastructural examination, functional assessments including grip strength testing, and immunological evaluations to characterize local and systemic responses. <b>Results:</b> Intramuscular vaccination induced localized injury characterized by inflammation, mitochondrial disruption, and reduced grip strength in wild-type animals. Transcriptomic and ultrastructural analyses revealed denervation-associated changes, downregulation of mitochondrial genes, cristae disruption, and activation of immune and apoptotic pathways. ApoE-deficient mice, particularly under Western diet conditions, demonstrated protection from mitochondrial and inflammatory responses despite comparable vaccine expression levels. This protection involved attenuated mitochondrial gene downregulation, preserved mitochondrial DNA integrity, and reduced inflammatory responses. While ApoE deficiency resulted in diminished antibody production, T cell responses remained intact, indicating selective immunomodulation. Cardiac tissue showed minimal transcriptional changes, confirming injection site-specific effects. <b>Conclusions:</b> ApoE deficiency provides protection against vaccine-induced mitochondrial and inflammatory damage at the injection site, with enhanced protective effects under metabolic stress conditions. These findings reveal important interactions between metabolic status, lipid metabolism, and local vaccine responses that may inform vaccination strategies in different patient populations.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"8964-8984"},"PeriodicalIF":13.3000,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439255/pdf/","citationCount":"0","resultStr":"{\"title\":\"ApoE deficiency protects from mRNA vaccine-induced mitochondrial dysfunction at the injection site under metabolic stress.\",\"authors\":\"Sun-Hee Cho, Byeongkwon Choi, Jisun Lee, Yu-Sun Lee, Mi-Ock Baek, You-Jeung Lee, Chae-Ok Gil, Min-Kyung Choi, Sana Abdul Khaliq, Syeda Maham, Jae-Kyung Hyun, Gahyun Roh, Huijeong Choi, Sowon Lee, Seo-Hyeon Bae, Seonghyun Lee, Hyo-Jung Park, Jae-Hun Ahn, Na-Young Lee, Byeong-Cheol Kang, Young Kyo Seo, Byung-Kwan Lim, Jae-Hwan Nam, Mina Rho, Mee-Sup Yoon\",\"doi\":\"10.7150/thno.119545\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Rationale:</b> The local tissue effects of mRNA vaccination remain incompletely understood. We investigated how SARS-CoV-2 mRNA vaccination impacts injection site tissues in the context of different metabolic states and apolipoprotein E (ApoE) status. <b>Methods:</b> We administered intramuscular SARS-CoV-2 mRNA vaccination to wild-type and ApoE-deficient mice under regular and high-fat diets, as well as macaques. We performed transcriptomic analysis, ultrastructural examination, functional assessments including grip strength testing, and immunological evaluations to characterize local and systemic responses. <b>Results:</b> Intramuscular vaccination induced localized injury characterized by inflammation, mitochondrial disruption, and reduced grip strength in wild-type animals. Transcriptomic and ultrastructural analyses revealed denervation-associated changes, downregulation of mitochondrial genes, cristae disruption, and activation of immune and apoptotic pathways. ApoE-deficient mice, particularly under Western diet conditions, demonstrated protection from mitochondrial and inflammatory responses despite comparable vaccine expression levels. This protection involved attenuated mitochondrial gene downregulation, preserved mitochondrial DNA integrity, and reduced inflammatory responses. While ApoE deficiency resulted in diminished antibody production, T cell responses remained intact, indicating selective immunomodulation. Cardiac tissue showed minimal transcriptional changes, confirming injection site-specific effects. <b>Conclusions:</b> ApoE deficiency provides protection against vaccine-induced mitochondrial and inflammatory damage at the injection site, with enhanced protective effects under metabolic stress conditions. These findings reveal important interactions between metabolic status, lipid metabolism, and local vaccine responses that may inform vaccination strategies in different patient populations.</p>\",\"PeriodicalId\":22932,\"journal\":{\"name\":\"Theranostics\",\"volume\":\"15 17\",\"pages\":\"8964-8984\"},\"PeriodicalIF\":13.3000,\"publicationDate\":\"2025-08-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439255/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Theranostics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.7150/thno.119545\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.119545","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
ApoE deficiency protects from mRNA vaccine-induced mitochondrial dysfunction at the injection site under metabolic stress.
Rationale: The local tissue effects of mRNA vaccination remain incompletely understood. We investigated how SARS-CoV-2 mRNA vaccination impacts injection site tissues in the context of different metabolic states and apolipoprotein E (ApoE) status. Methods: We administered intramuscular SARS-CoV-2 mRNA vaccination to wild-type and ApoE-deficient mice under regular and high-fat diets, as well as macaques. We performed transcriptomic analysis, ultrastructural examination, functional assessments including grip strength testing, and immunological evaluations to characterize local and systemic responses. Results: Intramuscular vaccination induced localized injury characterized by inflammation, mitochondrial disruption, and reduced grip strength in wild-type animals. Transcriptomic and ultrastructural analyses revealed denervation-associated changes, downregulation of mitochondrial genes, cristae disruption, and activation of immune and apoptotic pathways. ApoE-deficient mice, particularly under Western diet conditions, demonstrated protection from mitochondrial and inflammatory responses despite comparable vaccine expression levels. This protection involved attenuated mitochondrial gene downregulation, preserved mitochondrial DNA integrity, and reduced inflammatory responses. While ApoE deficiency resulted in diminished antibody production, T cell responses remained intact, indicating selective immunomodulation. Cardiac tissue showed minimal transcriptional changes, confirming injection site-specific effects. Conclusions: ApoE deficiency provides protection against vaccine-induced mitochondrial and inflammatory damage at the injection site, with enhanced protective effects under metabolic stress conditions. These findings reveal important interactions between metabolic status, lipid metabolism, and local vaccine responses that may inform vaccination strategies in different patient populations.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.