Testosterone exacerbates neutrophilia and cardiac injury in myocardial infarction via actions in bone marrow
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 bl...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56217-x |
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| author | 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 Gullestad Brage Høyem Amundsen Geir Øystein Andersen Mikael C. I. Karlsson Malin Hagberg Thulin Alessandro Camponeschi Dana Trompet Ola Hammarsten Björn Redfors Jan Borén Elmir Omerovic Malin C. Levin Andrei S. Chagin Tuva B. Dahl Åsa Tivesten |
| author_facet | 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 Gullestad Brage Høyem Amundsen Geir Øystein Andersen Mikael C. I. Karlsson Malin Hagberg Thulin Alessandro Camponeschi Dana Trompet Ola Hammarsten Björn Redfors Jan Borén Elmir Omerovic Malin C. Levin Andrei S. Chagin Tuva B. Dahl Åsa Tivesten |
| author_sort | Elin Svedlund Eriksson |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-5c4e935c58414afbbcfe34c19980b373 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-5c4e935c58414afbbcfe34c19980b3732025-02-09T12:44:37ZengNature PortfolioNature Communications2041-17232025-02-0116111610.1038/s41467-025-56217-xTestosterone exacerbates neutrophilia and cardiac injury in myocardial infarction via actions in bone marrowElin Svedlund Eriksson0Marta Lantero Rodriguez1Bente Halvorsen2Inger Johansson3Anna K. F. Mårtensson4Anna S. Wilhelmson5Camilla Huse6Thor Ueland7Pål Aukrust8Kaspar Broch9Lars Gullestad10Brage Høyem Amundsen11Geir Øystein Andersen12Mikael C. I. Karlsson13Malin Hagberg Thulin14Alessandro Camponeschi15Dana Trompet16Ola Hammarsten17Björn Redfors18Jan Borén19Elmir Omerovic20Malin C. Levin21Andrei S. Chagin22Tuva B. Dahl23Åsa Tivesten24Wallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of GothenburgWallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of GothenburgResearch Institute of Internal Medicine, Oslo University Hospital RikshospitaletWallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of GothenburgWallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of GothenburgWallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of GothenburgResearch Institute of Internal Medicine, Oslo University Hospital RikshospitaletResearch Institute of Internal Medicine, Oslo University Hospital RikshospitaletResearch Institute of Internal Medicine, Oslo University Hospital RikshospitaletDepartment of Cardiology, Oslo University Hospital RikshospitaletFaculty of Medicine, Institute of Clinical Medicine, University of OsloClinic of Cardiology, St. Olav’s Hospital, Trondheim University HospitalDepartment of Cardiology, Oslo University Hospital UllevålDepartment of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Karolinska University HospitalDepartment of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of GothenburgDepartment of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at University of GothenburgDepartment of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of GothenburgDepartment of Laboratory Medicine, Institute of Biomedicine, University of GothenburgWallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of GothenburgWallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of GothenburgWallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of GothenburgWallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of GothenburgDepartment of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of GothenburgResearch Institute of Internal Medicine, Oslo University Hospital RikshospitaletWallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of GothenburgAbstract 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.https://doi.org/10.1038/s41467-025-56217-x |
| spellingShingle | 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 Gullestad Brage Høyem Amundsen Geir Øystein Andersen Mikael C. I. Karlsson Malin Hagberg Thulin Alessandro Camponeschi Dana Trompet Ola Hammarsten Björn Redfors Jan Borén Elmir Omerovic Malin C. Levin Andrei S. Chagin Tuva B. Dahl Åsa Tivesten Testosterone exacerbates neutrophilia and cardiac injury in myocardial infarction via actions in bone marrow Nature Communications |
| title | Testosterone exacerbates neutrophilia and cardiac injury in myocardial infarction via actions in bone marrow |
| title_full | Testosterone exacerbates neutrophilia and cardiac injury in myocardial infarction via actions in bone marrow |
| title_fullStr | Testosterone exacerbates neutrophilia and cardiac injury in myocardial infarction via actions in bone marrow |
| title_full_unstemmed | Testosterone exacerbates neutrophilia and cardiac injury in myocardial infarction via actions in bone marrow |
| title_short | Testosterone exacerbates neutrophilia and cardiac injury in myocardial infarction via actions in bone marrow |
| title_sort | testosterone exacerbates neutrophilia and cardiac injury in myocardial infarction via actions in bone marrow |
| url | https://doi.org/10.1038/s41467-025-56217-x |
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