Free radical biology & medicine · 2025
Astragaloside IV alleviates myocardial injury in multidrug-resistant Klebsiella pneumoniae sepsis by targeting dendritic cell-associated C-type lectin-1 to improve macrophage mitochondrial function and polarization.
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Wan Mengzhi, Zhou Jing, Xiong Weichuan, Zou Juntao, You Luxia, Cheng Na
Аннотация
OBJECTIVE: The present study aims to determine whether astragaloside IV (ASIV) alleviates myocardial injury in juvenile mice with multidrug-resistant Klebsiella pneumoniae (MDR-KP) sepsis by targeting dendritic cell-associated C-type lectin-1 (Dectin-1), thereby restoring macrophage mitochondrial function and inhibiting pro-inflammatory M1 polarization.
METHODS: In vitro, macrophage polarization was evaluated using flow cytometry (iNOS/CD86 for M1; Arg-1/CD206 for M2). Mitochondrial membrane potential and mitochondrial reactive oxygen species (ROS) were assessed using JC-1 and 2',7'-dichlorodihydrofluorescein diacetate (DCF-DA) staining. In vivo, a murine model of sepsis was employed to assess cardiac function (ECG, echocardiography), myocardial enzymes, and neutrophil infiltration. RNA-seq and bioinformatics analysis were conducted to identify Dectin-1-linked pathways (NF-κB/MAPK), followed by gain- and loss-of-function validation.
RESULTS: ASIV enhanced M2 polarization, reduced ROS, and preserved mitochondrial integrity in vitro. In septic mice, ASIV improved cardiac output, decreased troponin-I/CK-MB, and attenuated neutrophil recruitment. Transcriptomics revealed ASIV downregulated Dectin-1 and its downstream NF-κB/MAPK cascades. Dectin-1 knockout confirmed its pivotal role in mediating ASIV's cardioprotection.
CONCLUSION: ASIV mitigates MDR-KP sepsis-induced myocardial injury by suppressing Dectin-1, thereby improving mitochondrial function, skewing macrophages toward an M2 phenotype, and reducing neutrophilic inflammation. These findings support the therapeutic potential of ASIV in the management of sepsis-associated cardiac dysfunction.
METHODS: In vitro, macrophage polarization was evaluated using flow cytometry (iNOS/CD86 for M1; Arg-1/CD206 for M2). Mitochondrial membrane potential and mitochondrial reactive oxygen species (ROS) were assessed using JC-1 and 2',7'-dichlorodihydrofluorescein diacetate (DCF-DA) staining. In vivo, a murine model of sepsis was employed to assess cardiac function (ECG, echocardiography), myocardial enzymes, and neutrophil infiltration. RNA-seq and bioinformatics analysis were conducted to identify Dectin-1-linked pathways (NF-κB/MAPK), followed by gain- and loss-of-function validation.
RESULTS: ASIV enhanced M2 polarization, reduced ROS, and preserved mitochondrial integrity in vitro. In septic mice, ASIV improved cardiac output, decreased troponin-I/CK-MB, and attenuated neutrophil recruitment. Transcriptomics revealed ASIV downregulated Dectin-1 and its downstream NF-κB/MAPK cascades. Dectin-1 knockout confirmed its pivotal role in mediating ASIV's cardioprotection.
CONCLUSION: ASIV mitigates MDR-KP sepsis-induced myocardial injury by suppressing Dectin-1, thereby improving mitochondrial function, skewing macrophages toward an M2 phenotype, and reducing neutrophilic inflammation. These findings support the therapeutic potential of ASIV in the management of sepsis-associated cardiac dysfunction.