Targeting Intrinsic Immune Rhythms to Prevent Collateral Tissue Damage in Acute MI

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Summary of  Journal of Experimental Medicine https://doi.org/10.1084/jem.20250240 
Dr. Alejandra Aroca-Crevillén  et al.

Points

Researchers identified that the intrinsic circadian clock within neutrophils drives daily fluctuations in cytotoxic activity and significantly influences the severity of tissue damage following a heart attack.
The study demonstrated that plasma CXCL12 signaling through the CXCR4 receptor naturally inhibits this neutrophil clock and mitigates excessive inflammation during specific times of the day.
Treatment with the synthetic CXCR4 agonist ATI2341 successfully switched neutrophils to a protective nocturnal phenotype that accumulated in the wound core rather than damaging healthy tissue.
This pharmacological intervention significantly reduced myocardial infarct size and preserved long-term cardiac function in mice without impairing their ability to fight off bacterial or fungal infections.
Targeting circadian mechanisms offers a novel therapeutic strategy to limit reperfusion injury while avoiding the risks associated with broad neutrophil depletion or general immunosuppression.

Summary

This study investigated the role of the intrinsic neutrophil circadian clock in modulating the severity of myocardial infarction (MI) and subsequent tissue injury. Recognizing that neutrophils exhibit diurnal peaks in cytotoxic activity, researchers hypothesized that this mechanism drives the increased severity of cardiac damage observed in early-morning heart attacks. The team identified that plasma CXCL12, signaling through the CXCR4 receptor, acts as a natural checkpoint that inhibits this clock, thereby mitigating excessive inflammation during specific times of the day.

Using murine models, the investigators demonstrated that genetic deletion of the neutrophil clock or the expression of a hyperactive CXCR4 receptor prevented diurnal spikes in tissue injury. To translate this finding therapeutically, the researchers administered ATI2341, a synthetic CXCR4 agonist. This pharmacological intervention successfully transitioned neutrophils into a “night-like” permissive phenotype. Mechanistically, this phenotypic shift altered cellular migration, causing neutrophils to accumulate in the wound core rather than the periphery, which spared neighboring healthy cardiomyocytes from collateral apoptotic death.

The administration of ATI2341 resulted in a reduction of myocardial tissue damage and the preservation of cardiac function in the weeks following ischemia. Crucially, while the drug blunted the inflammatory response responsible for infarct expansion, it did not compromise the host’s ability to mount an effective defense against bacterial and fungal infections. These findings suggest that targeting the CXCL12-CXCR4 axis provides a viable therapeutic strategy to limit reperfusion injury without the immunosuppressive risks associated with broad neutrophil depletion.

Link to the article: https://rupress.org/jem/article/223/2/e20250240/278573/A-circadian-checkpoint-relocates-neutrophils-to

References

Aroca-Crevillén, A., Martín-Salamanca, S., Torres, L. S., Crainiciuc, G., Sicilia, J., Peñaloza-Martínez, E., Rosillo, N., Molina-Moreno, M., Adrover, J. M., Rubio-Ponce, A., Vicanolo, T., Liu, X., Wichapong, K., Núñez, V., Balabanian, K., Bachelerie, F., Sancho, D., Casanova-Acebes, M., Ortiz-Pérez, J. T., … Hidalgo, A. (2026). A circadian checkpoint relocates neutrophils to minimize injury. Journal of Experimental Medicine, 223(2), e20250240. https://doi.org/10.1084/jem.20250240