Lai Xin, Wu Aimin, Liu Yao, Liu Chen, Chen Junzhou, Gu Ke, Yu Bing, Yan Hui, Luo Junqiu, Zheng Ping, Yu Jie, Chen Daiwen
Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China.
Key Laboratory for Animal Disease-resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China.
Int J Biol Sci. 2025 Jul 11;21(10):4567-4585. doi: 10.7150/ijbs.114545. eCollection 2025.
Macrophages exhibit heterogeneity due to their presence in different tissues that have distinct cell fates. Ferroptosis is one type of cellular fate, but the sensitivity of different types of macrophages to ferroptosis and the associated molecular mechanisms are not clear. This study explored the ferroptosis sensitivity of bone marrow and splenic macrophage, focusing on the contribution of ferritinophagy. We found that bone marrow M2 macrophages were more susceptible to ferroptosis, which was attributed to their lower solute carrier family 40 member 1 (SLC40A1) and ferritin heavy/light chain (FTH/L) expression and higher labile iron levels compared to those of splenic macrophages. Further, ferritinophagy activation, particularly in M2 macrophages, was identified as the primary cause of increased labile iron levels, as evidenced by experiments using autophagic flux modifiers and RAW264.7 cells with autophagy related 5 (ATG5) and nuclear receptor coactivator 4 (NCOA4) knockdown and NCOA4 knockout. These results provide a new direction for further understanding the heterogeneity and functionality of macrophages, and offers innovative treatments for a variety of health issues in which macrophage regulation plays a critical role.
由于巨噬细胞存在于具有不同细胞命运的不同组织中，因此表现出异质性。铁死亡是一种细胞命运类型，但不同类型的巨噬细胞对铁死亡的敏感性及其相关分子机制尚不清楚。本研究探讨了骨髓和脾脏巨噬细胞的铁死亡敏感性，重点关注铁自噬的作用。我们发现骨髓M2巨噬细胞对铁死亡更敏感，这归因于与脾脏巨噬细胞相比，它们的溶质载体家族40成员1（SLC40A1）和铁蛋白重/轻链（FTH/L）表达较低，不稳定铁水平较高。此外，铁自噬激活，特别是在M2巨噬细胞中，被确定为不稳定铁水平升高的主要原因，使用自噬通量调节剂以及自噬相关5（ATG5）和核受体辅激活因子4（NCOA4）敲低和NCOA4敲除的RAW264.7细胞进行的实验证明了这一点。这些结果为进一步理解巨噬细胞的异质性和功能提供了新方向，并为巨噬细胞调节起关键作用的各种健康问题提供了创新治疗方法。
