巨噬细胞中HIF-1α/HMOX1介导的铁死亡加剧疟疾进展
HIF-1α/HMOX1-Mediated Ferroptosis in Macrophages Exacerbates Malaria Progression.
摘要(中文译文)
脾脏在抗疟疾免疫中发挥统筹作用，其巨噬细胞可吞噬被疟原虫感染的红细胞（iRBCs）。尽管调节性细胞死亡（RCD）已在多种疾病中被广泛研究，但脾巨噬细胞的调节性细胞死亡与疟疾感染进展之间的关系尚未被探索。在本研究中，我们发现疟原虫感染可触发脾巨噬细胞发生铁死亡，其特征为HMOX1异常上调并伴随HIF-1α下调。在机制上，HIF-1α信号的缺失无法抑制HMOX1的表达，导致铁过载。Fer-1在体外可抑制暴露于iRBC的巨噬细胞发生铁死亡。感染约氏疟原虫的小鼠脾巨噬细胞中铁死亡生物标志物升高，且可被Fer-1治疗逆转。此外，与GPX4感染小鼠相比，条件性敲除感染小鼠（GPX4 Lyz2Cre）表现出更差的健康状况和更严重的寄生虫血症。此外，在疟疾患者外周血单核细胞（PBMCs）来源的单核细胞中检测到相同的铁死亡特征，证实了跨物种保守性。总之，这些发现表明约氏疟原虫NSM感染可触发脾巨噬细胞铁死亡，从而加剧疟疾进展。靶向HIF-1α/HMOX1轴以调控巨噬细胞铁死亡可减轻疟原虫感染的进展，提供了关键的机制性见解，值得谨慎探索用于宿主导向干预。
Abstract
The spleen orchestrates anti-malarial immunity, with its macrophages phagocytizing Plasmodium-infected blood cells (iRBCs). While regulated cell death (RCD) has been extensively studied in various diseases, the relationship between regulatory cell death of splenic macrophages and the progression of malaria infection remains unexplored. In this study, we identify that Plasmodium infection triggers ferroptosis in splenic macrophages characterized by aberrant HMOX1 upregulation concomitant with HIF-1α downregulation. Mechanistically, the loss of HIF-1α signaling fails to restrain HMOX1 expression, leading to Fe overload. Fer-1 inhibits ferroptosis in iRBC-exposed macrophages in vitro. P. yoelii-infected mice show elevated ferroptosis biomarkers in splenic macrophages, reversible by Fer-1 treatment. Additionally, compared to GPX4 infected mice, the conditional knockout infected mice (GPX4 Lyz2Cre) display worsened health conditions and more severe parasitemia. Moreover, identical ferroptosis signature is detected in monocytes from malaria patient PBMCs, confirming cross-species conservation. In conclusion, these findings suggest that Plasmodium yoelii NSM infection triggers ferroptosis in splenic macrophages, which exacerbates malaria progression. Targeting the HIF-1α/HMOX1 axis to modulate macrophage ferroptosis alleviates the progression of Plasmodium infection, providing crucial mechanistic insights that warrant cautious exploration for host-directed interventions.
如何引用
AMA
Guikuan Liang, Jiajie Li, Xiongyu Xie, Haiwen Yuan, Wei Xiao, Mingjie Chen, et al. HIF-1α/HMOX1-Mediated Ferroptosis in Macrophages Exacerbates Malaria Progression.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2026; doi:10.1096/fj.202504265RR.
APA
Guikuan Liang, Jiajie Li, Xiongyu Xie, Haiwen Yuan, Wei Xiao, Mingjie Chen, et al (2026). HIF-1α/HMOX1-Mediated Ferroptosis in Macrophages Exacerbates Malaria Progression.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. https://doi.org/10.1096/fj.202504265RR
GB/T 7714
Guikuan Liang, Jiajie Li, Xiongyu Xie, Haiwen Yuan, Wei Xiao, Mingjie Chen, et al. HIF-1α/HMOX1-Mediated Ferroptosis in Macrophages Exacerbates Malaria Progression.[J]. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026 doi:10.1096/fj.202504265RR.
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