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

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 CD11bLy6Cmonocyte 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.