Inhibition of inflammatory factor TNF-α by ferrostatin-1 in microglia regulates necroptosis of oligodendrocyte precursor cells

  • Neuroreport. 2023 Aug 24;34(11):583-591. doi: 10.1097/WNR.0000000000001928.
Zhi Chai  1  2 ,  Teng Ma  1 ,  Yunhong Li  1  3 ,  Qiuyuan Chen  1 ,  Yali Kang  1 ,  Jinping Sun  1 ,  Tao Peng  1 ,  Nina Wang  1 ,  Chengjun Yu  1 ,  Lijuan Wang  1 ,  Xiaolin Hou  4 ,  Wei Wang  4 ,  Yin Wang  1
Affiliations
  • 1. Department of Physiology and Neurobiology, Basic Medical School of Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, Ningxia.
  • 2. Department of Clinical Laboratory, Xi'an Daxing Hospital, Xi'an.
  • 3. Scientific Technology Center of Ningxia Medical University.
  • 4. Department of Neurology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China.
PMID: 37384932 DOI: 10.1097/WNR.0000000000001928
Abstract

Objective: Inflammation of the surrounding environment is a major reason causing loss or injury of oligodendrocyte precursor cells (OPCs) in myelin-associated diseases. Lipopolysaccharide-activated microglia can release various inflammatory factors such as tumor necrosis factor-α (TNF-α). One of the ways of OPC death is Necroptosis, which can be triggered by TNF-α, a death receptor ligand, by activating receptor-interacting protein kinase 1 (RIPK1)/RIPK3/Mixed Lineage Kinase domain-like protein (MLKL) signaling pathway. This study investigated whether inhibiting microglia Ferroptosis can decrease TNF-α release to alleviate OPC Necroptosis.

Methods: Lipopolysaccharide and Fer-1 stimulate BV2 cells. The expressions of GPX4 and TNF-α were detected by western blot and quantitative real-time PCR; malondialdehyde, glutathione, iron, and Reactive Oxygen Species were measured by the assay kits. After lipopolysaccharide stimulation of BV2 cells, the supernatant was taken to culture OPC. The protein expression levels of RIPK1, p-RIPK1, RIPK3, p-RIPK3, MLKL, and p-MLKL were detected by western blot.

Results: Lipopolysaccharide administration could induce Ferroptosis in microglia by decreasing Ferroptosis marker GPX4, while Ferroptosis inhibitor Fer-1 could significantly increase GPX4 level. Fer-1 prevented oxidative stress and iron concentration elevation and alleviated mitochondrial damage in lipopolysaccharide-induced BV2 cells. The results revealed that Fer-1 downregulated the release of lipopolysaccharide-induced TNF-α in microglia and attenuated OPC Necroptosis by significantly decreasing the expression levels of RIPK1, p-RIPK1, MLKL, p-MLKL, RIPK3, and p-RIPK3.

Conclusion: Fer-1 may be a potential agent for inhibiting inflammation and treating myelin-related diseases.

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