Key result
Cardiac-specific sRAGE overexpression alleviates ischemia-reperfusion injury by recruiting regulatory T cells via CCL4.
Why the study?
Soluble receptors for advanced glycation end-products (sRAGE) are known to reduce myocardial ischemia-reperfusion injury (MIRI) by increasing regulatory T cells (Tregs), but the precise mechanism and the major chemokines recruiting Tregs during MIRI remained incompletely understood.
Does cardiac-specific sRAGE overexpression attenuate myocardial ischemia-reperfusion injury by recruiting regulatory T cells via the JNK/AP-1/CCL4 pathway in preclinical mouse and in vitro cardiomyocyte models?
Does cardiac-specific sRAGE overexpression attenuate myocardial ischemia-reperfusion injury by recruiting regulatory T cells via the JNK/AP-1/CCL4 pathway in preclinical mouse and in vitro cardiomyocyte models?
This preclinical study demonstrates that sRAGE alleviates myocardial ischemia-reperfusion injury by promoting cardiomyocyte CCL4 secretion via the JNK/AP-1 pathway to recruit regulatory T cells, identifying a potential immunotherapeutic target.
Answers are grounded in this paper and cite their sources.
sRAGE effects on Tregs in MIRI need human validation; leaves open the dominant chemokine driving recruitment.
Background Immune response has recently been shown to play a crucial role in myocardial ischemia-reperfusion (MIR). Our previous studies have confirmed that soluble receptors for advanced glycation end-products (sRAGE) could reduce myocardial ischemia-reperfusion injury (MIRI) by increasing the number of regulatory T cells (Tregs). However, the precise mechanism is still incompletely understood. Purpose The present study aimed to determine which kind of chemokines play a major role in recruiting Tregs during MIRI. The potential mechanism of sRAGE on the chemokine production was further explored. Methods We modeled mice with cardiac-specific overexpression of sRAGE by crossing the floxed sRAGE mouse model with the cardiomyocyte-specific Cre transgenic mouse. Experimental models were established utilizing left anterior descending coronary artery ligation in mice and oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro. Transcriptomics, quantitative real-time polymerase chain reaction, immunohistochemistry, flow cytometry, and western blotting were used to determine the chemokines and related pathways involved in the recruitment of Tregs during MIRI. Results Using transcriptomics, quantitative real-time polymerase chain reaction, and western blotting approach, we identify the chemokine CCL4 plays a crucial role during regulatory T cell recruitment in the heart after MIRI. In vivo studies show that depletion of CCL4 reduces Tregs infiltration into the ischemic myocardium, subsequently deteriorating cardiac injury post-MIR. Mechanistically, sRAGE promotes cardiomyocytes to express and secrete CCL4 via the JNK/AP-1 pathway in vitro. Selective inhibition of the JNK/AP-1 pathway could decrease CCL4 production in sRAGE overexpression cardiomyocytes. Conclusions sRAGE induces Tregs recruitment and alleviates MIRI via the JNK/AP-1/CCL4 pathway, preserving myocardial function and impeding inflammation and apoptosis, providing new perspectives for immunotherapeutic targets in MIRI treatment.
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Jiang et al. (2024) studied Myocardial ischemia-reperfusion injury (MIRI). Cardiac-specific sRAGE overexpression, CCL4 depletion, and selective JNK/AP-1 pathway inhibition was evaluated on Regulatory T cell (Treg) recruitment, CCL4 expression, and myocardial ischemia-reperfusion injury. Cardiac-specific sRAGE overexpression alleviated myocardial ischemia-reperfusion injury by recruiting regulatory T cells via the JNK/AP-1/CCL4 pathway.
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