Lipocalin-2 inhibition alleviates neural injury by microglia ferroptosis suppression after experimental intracerebral hemorrhage in mice via enhancing ferritin light chain expression

  • Biochim Biophys Acta Mol Basis Dis. 2024 Oct;1870(7):167435. doi: 10.1016/j.bbadis.2024.167435.
Xiaowei Fei  1 ,  Yanan Dou  1 ,  Yuefan Yang  1 ,  Buyi Zheng  2 ,  Peng Luo  1 ,  Shuhui Dai  1 ,  Jingwei Zhang  3 ,  Kang Peng  4 ,  Xiaofan Jiang  1 ,  Yang Yu  1 ,  Jialiang Wei  5
Affiliations
  • 1. Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
  • 2. Department of Neurosurgery, Wenzhou People's Hospital, Wenzhou, Zhejiang, China.
  • 3. Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
  • 4. Department of Radiology, Xiangya Hospital, Central South University, Changsha, China.
  • 5. Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Department of Health Service, Fourth Military Medical University, Xi'an, China. Electronic address: [email protected].
PMID: 39067535 DOI: 10.1016/j.bbadis.2024.167435
Abstract

Introduction: Microglia play pivotal roles in post-intracerebral hemorrhage (ICH) neural injury. Iron metabolism, which is dysregulated after ICH, participates in microglial dysfunction. Previous studies have shown that iron metabolism-related lipocalin-2 (LCN2) is involved in regulating microglial function following ICH. In this study, we investigated the role of LCN2 in microglial function following ICH.

Methods: The BV2 (microglia) cell line, transfected with LCN2 for overexpression/interference, received a blood infusion from C57BL/6 mice in vitro. For the in vivo study of LCN2 function, an LCN2 knockout was conducted in mice. Liproxstatin-1 and RSL3 were used to manipulate Ferroptosis and to study the effects of LCN2 on microglia after ICH. A BV2 (microglia) cell line, transfected with ferritin light chain (FTL) for overexpression/interference, was co-cultured with primary cultured neurons for a study on the mechanism of LCN2. Behavioral tests were conducted pre-ICH and on days 3, 7, and 28 post-ICH, and the brains and cultured cells were collected for protein, histological, and morphological studies.

Results: Brain LCN2 expression was upregulated in microglia, astrocytes, and neurons and played hazardous roles after ICH. In microglia, LCN2 promoted Ferroptosis, which facilitated neural injury after ICH. LCN2-mediated FTL deficiency was shown to be responsible for microglial ferroptosis-induced neural injury.

Conclusion: Our study suggests that LCN2-enhanced microglial Ferroptosis plays a detrimental role by inducing FTL deficiency after ICH. The current study reveals a novel molecular mechanism involved in the pathophysiological progression of ICH.

Keywords
Ferritin light chain; Ferroptosis; Intracerebral hemorrhage; Lipocalin-2; Microglia.
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