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

IF 14.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Nature Communications Pub Date : 2025-02-05 DOI:10.1038/s41467-025-56217-x

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

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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.

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.