IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-56217-x.html
   My bibliography  Save this article

Testosterone exacerbates neutrophilia and cardiac injury in myocardial infarction via actions in bone marrow

Author

Listed:
  • Elin Svedlund Eriksson

    (Sahlgrenska Academy at University of Gothenburg)

  • Marta Lantero Rodriguez

    (Sahlgrenska Academy at University of Gothenburg)

  • Bente Halvorsen

    (Oslo University Hospital Rikshospitalet
    University of Oslo)

  • Inger Johansson

    (Sahlgrenska Academy at University of Gothenburg)

  • Anna K. F. Mårtensson

    (Sahlgrenska Academy at University of Gothenburg)

  • Anna S. Wilhelmson

    (Sahlgrenska Academy at University of Gothenburg
    Copenhagen University Hospital - Rigshospitalet
    University of Copenhagen)

  • Camilla Huse

    (Oslo University Hospital Rikshospitalet
    University of Oslo
    Harvard Medical School)

  • Thor Ueland

    (Oslo University Hospital Rikshospitalet
    University of Oslo
    University Hospital of North Norway)

  • Pål Aukrust

    (Oslo University Hospital Rikshospitalet
    University of Oslo)

  • Kaspar Broch

    (Oslo University Hospital Rikshospitalet
    University of Oslo)

  • Lars Gullestad

    (University of Oslo
    Oslo University Hospital Rikshospitalet
    University of Oslo)

  • Brage Høyem Amundsen

    (Trondheim University Hospital
    Norwegian University of Science and Technology (NTNU))

  • Geir Øystein Andersen

    (Oslo University Hospital Ullevål)

  • Mikael C. I. Karlsson

    (Karolinska University Hospital)

  • Malin Hagberg Thulin

    (University of Gothenburg)

  • Alessandro Camponeschi

    (Sahlgrenska Academy at University of Gothenburg
    Sahlgrenska University Hospital)

  • Dana Trompet

    (University of Gothenburg
    Karolinska Institute)

  • Ola Hammarsten

    (University of Gothenburg)

  • Björn Redfors

    (Sahlgrenska Academy at University of Gothenburg)

  • Jan Borén

    (Sahlgrenska Academy at University of Gothenburg)

  • Elmir Omerovic

    (Sahlgrenska Academy at University of Gothenburg)

  • Malin C. Levin

    (Sahlgrenska Academy at University of Gothenburg)

  • Andrei S. Chagin

    (University of Gothenburg)

  • Tuva B. Dahl

    (Oslo University Hospital Rikshospitalet)

  • Åsa Tivesten

    (Sahlgrenska Academy at University of Gothenburg
    Region Västra Götaland)

Abstract

Men develop larger infarct sizes than women after a myocardial infarction (MI), but the mechanism underlying this sex difference is unknown. Here, we demonstrated that blood neutrophil counts post-MI were higher in male than female mice. Castration-induced testosterone deficiency reduced blood neutrophil counts to the level in females and increased survival post-MI. These effects were mimicked by Osterix-directed ablation of the androgen receptor in bone marrow (BM). Mechanistically, androgens downregulated the leukocyte retention factor CXCL12 in BM stromal cells. Post-hoc analysis of clinical trial data showed that neutrophilia was greater in men than women after reperfusion of first-time ST-elevation MI, and tocilizumab, an interleukin-6 receptor inhibitor, reduced blood neutrophil counts and infarct size to a greater extent in men than women. Our work reveals a previously unknown mechanism connecting testosterone with neutrophilia and MI injury via BM and identifies the importance of considering sex when developing anti-inflammatory strategies to treat MI.

Suggested Citation

  • Elin Svedlund Eriksson & Marta Lantero Rodriguez & Bente Halvorsen & Inger Johansson & Anna K. F. Mårtensson & Anna S. Wilhelmson & Camilla Huse & Thor Ueland & Pål Aukrust & Kaspar Broch & Lars Gulle, 2025. "Testosterone exacerbates neutrophilia and cardiac injury in myocardial infarction via actions in bone marrow," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56217-x
    DOI: 10.1038/s41467-025-56217-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-56217-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-56217-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Fei Li & Xudong Xing & Qiqi Jin & Xiang-Ming Wang & Pengfei Dai & Ming Han & Huili Shi & Ze Zhang & Xianlong Shao & Yunyi Peng & Yiqin Zhu & Jiayi Xu & Dan Li & Yu Chen & Wei Wu & Qiao Wang & Chen Yu , 2024. "Sex differences orchestrated by androgens at single-cell resolution," Nature, Nature, vol. 629(8010), pages 193-200, May.
    2. Janet L. Markman & Rebecca A. Porritt & Daiko Wakita & Malcolm E. Lane & Daisy Martinon & Magali Noval Rivas & Michael Luu & Edwin M. Posadas & Timothy R. Crother & Moshe Arditi, 2020. "Loss of testosterone impairs anti-tumor neutrophil function," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    3. Adam Greenbaum & Yen-Michael S. Hsu & Ryan B. Day & Laura G. Schuettpelz & Matthew J. Christopher & Joshua N. Borgerding & Takashi Nagasawa & Daniel C. Link, 2013. "CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance," Nature, Nature, vol. 495(7440), pages 227-230, March.
    4. Fei Li & Xudong Xing & Qiqi Jin & Xiang-Ming Wang & Pengfei Dai & Ming Han & Huili Shi & Ze Zhang & Xianlong Shao & Yunyi Peng & Yiqin Zhu & Jiayi Xu & Dan Li & Yu Chen & Wei Wu & Qiao Wang & Chen Yu , 2024. "Publisher Correction: Sex differences orchestrated by androgens at single-cell resolution," Nature, Nature, vol. 631(8019), pages 6-6, July.
    5. Koichi Akashi & David Traver & Toshihiro Miyamoto & Irving L. Weissman, 2000. "A clonogenic common myeloid progenitor that gives rise to all myeloid lineages," Nature, Nature, vol. 404(6774), pages 193-197, March.
    6. Alvaro Gomariz & Patrick M. Helbling & Stephan Isringhausen & Ute Suessbier & Anton Becker & Andreas Boss & Takashi Nagasawa & Grégory Paul & Orcun Goksel & Gábor Székely & Szymon Stoma & Simon F. Nør, 2018. "Quantitative spatial analysis of haematopoiesis-regulating stromal cells in the bone marrow microenvironment by 3D microscopy," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yoshiki Omatsu & Shota Aiba & Tomonori Maeta & Kei Higaki & Kazunari Aoki & Hitomi Watanabe & Gen Kondoh & Riko Nishimura & Shu Takeda & Ung-il Chung & Takashi Nagasawa, 2022. "Runx1 and Runx2 inhibit fibrotic conversion of cellular niches for hematopoietic stem cells," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Kiyoka Saito & Mark Garde & Terumasa Umemoto & Natsumi Miharada & Julia Sjöberg & Valgardur Sigurdsson & Haruki Shirozu & Shunsuke Kamei & Visnja Radulovic & Mitsuyoshi Suzuki & Satoshi Nakano & Stefa, 2024. "Lipoprotein metabolism mediates hematopoietic stem cell responses under acute anemic conditions," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Yang Liu & Qi Chen & Hyun-Woo Jeong & Bong Ihn Koh & Emma C. Watson & Cong Xu & Martin Stehling & Bin Zhou & Ralf H. Adams, 2022. "A specialized bone marrow microenvironment for fetal haematopoiesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Linghua Zhou & Yong Shen & Libo Jiang & Danni Yin & Jingxin Guo & Hui Zheng & Hao Sun & Rongling Wu & Yunqian Guo, 2015. "Systems Mapping for Hematopoietic Progenitor Cell Heterogeneity," PLOS ONE, Public Library of Science, vol. 10(5), pages 1-18, May.
    5. Yang Ping Kuo & César Nombela-Arrieta & Oana Carja, 2024. "A theory of evolutionary dynamics on any complex population structure reveals stem cell niche architecture as a spatial suppressor of selection," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Runfeng Miao & Harim Chun & Xing Feng & Ana Cordeiro Gomes & Jungmin Choi & João P. Pereira, 2022. "Competition between hematopoietic stem and progenitor cells controls hematopoietic stem cell compartment size," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    7. Christina M. Termini & Amara Pang & Tiancheng Fang & Martina Roos & Vivian Y. Chang & Yurun Zhang & Nicollette J. Setiawan & Lia Signaevskaia & Michelle Li & Mindy M. Kim & Orel Tabibi & Paulina K. Li, 2021. "Neuropilin 1 regulates bone marrow vascular regeneration and hematopoietic reconstitution," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    8. Georgia K. Atkin-Smith & Jascinta P. Santavanond & Amanda Light & Joel S. Rimes & Andre L. Samson & Jeremy Er & Joy Liu & Darryl N. Johnson & Mélanie Le Page & Pradeep Rajasekhar & Raymond K. H. Yip &, 2024. "In situ visualization of endothelial cell-derived extracellular vesicle formation in steady state and malignant conditions," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    9. Xiaolan Liu & Xufeng Cen & Ronghai Wu & Ziyan Chen & Yanqi Xie & Fengqi Wang & Bing Shan & Linghui Zeng & Jichun Zhou & Bojian Xie & Yangjun Cai & Jinyan Huang & Yingjiqiong Liang & Youqian Wu & Chao , 2023. "ARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    10. Bin Zhang & Dandan Zhao & Fang Chen & David Frankhouser & Huafeng Wang & Khyatiben V. Pathak & Lei Dong & Anakaren Torres & Krystine Garcia-Mansfield & Yi Zhang & Dinh Hoa Hoang & Min-Hsuan Chen & Shu, 2023. "Acquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    11. Raymond K. H. Yip & Joel S. Rimes & Bianca D. Capaldo & François Vaillant & Kellie A. Mouchemore & Bhupinder Pal & Yunshun Chen & Elliot Surgenor & Andrew J. Murphy & Robin L. Anderson & Gordon K. Smy, 2021. "Mammary tumour cells remodel the bone marrow vascular microenvironment to support metastasis," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    12. Yuki Matsushita & Jialin Liu & Angel Ka Yan Chu & Chiaki Tsutsumi-Arai & Mizuki Nagata & Yuki Arai & Wanida Ono & Kouhei Yamamoto & Thomas L. Saunders & Joshua D. Welch & Noriaki Ono, 2023. "Bone marrow endosteal stem cells dictate active osteogenesis and aggressive tumorigenesis," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    13. Trent D. Hall & Hyunjin Kim & Mahmoud Dabbah & Jacquelyn A. Myers & Jeremy Chase Crawford & Antonio Morales-Hernandez & Claire E. Caprio & Pramika Sriram & Emilia Kooienga & Marta Derecka & Esther A. , 2022. "Murine fetal bone marrow does not support functional hematopoietic stem and progenitor cells until birth," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    14. Yoshito Yamada & Tuan Thanh Nguyen & Daniela Impellizzieri & Katsutaka Mineura & Rintaro Shibuya & Alvaro Gomariz & Martina Haberecker & Jakob Nilsson & César Nombela-Arrieta & Wolfgang Jungraithmayr , 2023. "Biased IL-2 signals induce Foxp3-rich pulmonary lymphoid structures and facilitate long-term lung allograft acceptance in mice," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    15. Jia Cao & Ling Jin & Zi-Qi Yan & Xiao-Kai Wang & You-You Li & Zun Wang & Yi-Wei Liu & Hong-Ming Li & Zhe Guan & Ze-Hui He & Jiang-Shan Gong & Jiang-Hua Liu & Hao Yin & Yi-Juan Tan & Chun-Gu Hong & Shi, 2023. "Reassessing endothelial-to-mesenchymal transition in mouse bone marrow: insights from lineage tracing models," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    16. Madison L. Doolittle & Dominik Saul & Japneet Kaur & Jennifer L. Rowsey & Stephanie J. Vos & Kevin D. Pavelko & Joshua N. Farr & David G. Monroe & Sundeep Khosla, 2023. "Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    17. Adrienne Anginot & Julie Nguyen & Zeina Abou Nader & Vincent Rondeau & Amélie Bonaud & Maria Kalogeraki & Antoine Boutin & Julia P. Lemos & Valeria Bisio & Joyce Koenen & Lea Hanna Doumit Sakr & Amand, 2023. "WHIM Syndrome-linked CXCR4 mutations drive osteoporosis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    18. Ritsuko Nakai & Takafumi Yokota & Masahiro Tokunaga & Mikiro Takaishi & Tomomasa Yokomizo & Takao Sudo & Henyun Shi & Yoshiaki Yasumizu & Daisuke Okuzaki & Chikara Kokubu & Sachiyo Tanaka & Katsuyoshi, 2024. "A newly identified gene Ahed plays essential roles in murine haematopoiesis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    19. Yinghui Li & Mei He & Wenshan Zhang & Wei Liu & Hui Xu & Ming Yang & Hexiao Zhang & Haiwei Liang & Wenjing Li & Zhaozhao Wu & Weichao Fu & Shiqi Xu & Xiaolei Liu & Sibin Fan & Liwei Zhou & Chaoqun Wan, 2023. "Expansion of human megakaryocyte-biased hematopoietic stem cells by biomimetic Microniche," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56217-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.