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Physical exercise mitigates chronic psychological stress-induced vascular inflammation via the BDNF-Kif4-TARM1 axis.

Overview

Authors: Xianghui Zheng1,2, Yunqi Li1,2, Peiyao Wang1,2, Zhou Guo1,2, Yuxuan Liu1,2, Qi Liu1,2, Baitao Wang1,2, Huiyu Wang1,2, Lizhi Zheng1,2, Cien Li1,2, Shuhong Liu1,2, Shiyu Wang1,2, Xinyu Hou1,2, Xiaojun Wu1,2, Yong Sun1,2, Bo Yu1,2,3, Yang Zheng1,2,3, Jian Wu1,2,3
ORCID iDs: Xianghui Zheng, Yunqi Li, Peiyao Wang, Yong Sun, Bo Yu, Yang Zheng, Jian Wu
  1. Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
  2. The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
  3. State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Harbin Medical University, Harbin, China
Institutions: Second Affiliated Hospital of Harbin Medical University (China); Harbin Medical University (China)
Journal: Clinical and translational medicine, volume 16, issue 4, article e70674
Dates: received 20 November 2025; accepted 11 April 2026; published online 20 April 2026; in print April 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1002/ctm2.70674 · PMID 42010994 · PMCID PMC13096691 · OpenAlex W7155053062
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism), cellular / molecular (subfield)
Methods: Statistics
Keywords: BDNF–Kif4–TARM1 axis, exercise, neuroimmune crosstalk, psychological stress, vascular inflammation
MeSH: Brain-Derived Neurotrophic Factor*, Inflammation*, Kinesins*, Physical Conditioning, Animal*, Stress, Psychological*, Animals, Disease Models, Animal, Humans, Male, Mice, Mice, Inbred C57BL (* major topic)
Topic: Cardiac Health and Mental Health (Cardiology and Cardiovascular Medicine, Medicine), according to OpenAlex
Funding: National Natural Science Foundation of China (82002376, 82172537, 82372565); Heilongjiang Provincial Universities Basic Scientific Research Business Expenses Scientific Research Project (2023-KYYWF-0174); The Natural Science Foundation of Heilongjiang Province of China (YQ2024H014); Heilongjiang Postdoctoral Fund (LBH-Z24290)
Citations: not cited yet (Europe PMC); 54 references in the paper

Abstract

Background: Chronic psychological stress drives neuroimmune crosstalk and accelerates atherosclerosis progression. Physical exercise confers broad health benefits and is associated with reduced inflammation. However, the exercise‐mediated factors and mechanisms that mitigate stress‐induced vascular inflammation remain unclear.

Methods: Chronic restraint stress (CRS) and voluntary exercise models were established to investigate the role of exercise in neuroimmune crosstalk. RNA sequencing identified kinesin family member 4 (Kif4) as a key gene associated with the attenuation of stress‐induced inflammatory responses in peripheral blood monocytes following exercise. Combined co‐immunoprecipitation–mass spectrometry and membrane proteomics identified T cell‐interacting activating receptors on myeloid cell 1 (TARM1) as the Kif4 cargo. The function of TARM1 was validated using an immobilized TARM1‐Fc fusion protein. Brain‐derived neurotrophic factor (BDNF), a key effector during exercise and stress, regulated the Kif4–TARM1 axis using recombinant BDNF (rBDNF) and the TrkB inhibitor ANA‐12. Finally, exercise‐mediated effects and mechanisms were examined in atherosclerotic CRS‐exposed mouse models and in patients with coronary artery disease (CAD) experiencing high psychological stress.

Results: Physical exercise alleviated stress‐induced neuroimmune crosstalk, reduced the proinflammatory CD11b+Ly6Chigh monocyte phenotype, and suppressed M1 macrophage polarization. Kif4 knockdown mitigated proinflammatory responses in peripheral blood monocytes and BMDMs in the CRS model mice. Mechanistically, kinesin Kif4 facilitates microtubule‐dependent transport of TARM1 to the plasma membrane, thereby promoting macrophage inflammatory responses and enhancing monocyte‒endothelial cell adhesion. Conversely, neurogenic BDNF, regulated by exercise and stress, activated the TrkB receptor in monocytes/macrophages and inhibited the p‐STAT3/Kif4/TARM1 signalling pathway. Furthermore, in both an atherosclerotic mouse model and patients with CAD, exercise mitigated stress‐induced inflammation via the BDNF–Kif4–TARM1 axis.

Conclusions: Physical exercise alleviates stress‐induced neuroimmune crosstalk through the BDNF–Kif4–TARM1 axis, revealing a novel neuroimmune‐mediated brain–heart axis that supports exercise‐based therapeutic strategies for psychogenic CAD.

Key Points: Chronic psychological stress drives systemic inflammation through neuroimmune mechanisms, thereby accelerating the progression of coronary artery disease (CAD).

Physical exercise alleviates stress‐induced neuroimmune crosstalk, partly by suppressing proinflammatory responses in monocytes/macrophages.

This study provides novel insights into exercise‐regulated neuroimmune mechanisms involving the monocyte BDNF–Kif4–TARM1 axis.

In both an atherosclerotic mouse model and patients with CAD, exercise mitigated stress‐induced inflammation via the BDNF–Kif4–TARM1 axis.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

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Data

Datasets cited

Data availability statement

The data underlying this article are available in the article and in its online supplementary material. All the data that support the findings of this study are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 18 authors, 5 keywords, 11 MeSH terms, 4 funders, 54 references.

Cite

This paper

Zheng, X., Li, Y., Wang, P., Guo, Z., Liu, Y., Liu, Q., Wang, B., Wang, H., Zheng, L., Li, C., Liu, S., Wang, S., Hou, X., Wu, X., Sun, Y., Yu, B., Zheng, Y., & Wu, J. (2026). Physical exercise mitigates chronic psychological stress-induced vascular inflammation via the BDNF-Kif4-TARM1 axis. Clinical and translational medicine, 16(4), e70674. https://doi.org/10.1002/ctm2.70674

BibTeX

@article{zheng2026physical,
author = {Zheng, Xianghui and Li, Yunqi and Wang, Peiyao and Guo, Zhou and Liu, Yuxuan and Liu, Qi and Wang, Baitao and Wang, Huiyu and Zheng, Lizhi and Li, Cien and Liu, Shuhong and Wang, Shiyu and Hou, Xinyu and Wu, Xiaojun and Sun, Yong and Yu, Bo and Zheng, Yang and Wu, Jian},
title = {{Physical exercise mitigates chronic psychological stress-induced vascular inflammation via the BDNF-Kif4-TARM1 axis}},
journal = {Clinical and translational medicine},
year = {2026},
month = apr,
volume = {16},
number = {4},
pages = {e70674},
publisher = {Wiley},
issn = {2001-1326},
doi = {10.1002/ctm2.70674},
url = {https://doi.org/10.1002/ctm2.70674},
pmid = {42010994},
pmcid = {PMC13096691}
}

RIS

TY - JOUR
AU - Zheng, Xianghui
AU - Li, Yunqi
AU - Wang, Peiyao
AU - Guo, Zhou
AU - Liu, Yuxuan
AU - Liu, Qi
AU - Wang, Baitao
AU - Wang, Huiyu
AU - Zheng, Lizhi
AU - Li, Cien
AU - Liu, Shuhong
AU - Wang, Shiyu
AU - Hou, Xinyu
AU - Wu, Xiaojun
AU - Sun, Yong
AU - Yu, Bo
AU - Zheng, Yang
AU - Wu, Jian
TI - Physical exercise mitigates chronic psychological stress-induced vascular inflammation via the BDNF-Kif4-TARM1 axis
T2 - Clinical and translational medicine
J2 - Clin Transl Med
PY - 2026
DA - 2026/04/01
VL - 16
IS - 4
SP - e70674
SN - 2001-1326
PB - Wiley
DO - 10.1002/ctm2.70674
UR - https://doi.org/10.1002/ctm2.70674
LA - en
ER -

CSL-JSON

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