Asparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence

Ouwen Qiu; Jianyi Zhao; Zhonggang Shi; Huan Li; Siyuan Wang; Keman Liao; Minchao Tang; Jieqiong Xie; Xi Huang; Wenrui Zhang; Li Zhou; Xi Yang; Zhiyi Zhou; Lei Xu; Renhua Huang; Yifeng Miao; Yongming Qiu; Yingying Lin

doi:10.1016/j.isci.2024.109698

Asparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence

iScience. 2024 Apr 9;27(5):109698. doi: 10.1016/j.isci.2024.109698. eCollection 2024 May 17.

Authors

Ouwen Qiu¹, Jianyi Zhao¹, Zhonggang Shi¹, Huan Li², Siyuan Wang¹, Keman Liao¹, Minchao Tang³, Jieqiong Xie⁴, Xi Huang⁵, Wenrui Zhang¹, Li Zhou¹, Xi Yang¹, Zhiyi Zhou¹, Lei Xu⁶, Renhua Huang⁶, Yifeng Miao⁷, Yongming Qiu¹, Yingying Lin¹

Affiliations

¹ Brain Injury Center, Shanghai Institute of Head Trauma, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, P.R. China.
² Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
³ Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Guangxi 530021, P.R. China.
⁴ Department of Neurology, The Second Affiliated Hospital of Guangxi Medical University, Guangxi 530007, P.R. China.
⁵ Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Guangxi 530021, P.R. China.
⁶ Department of Radiation, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, P.R. China.
⁷ Department of Neurosurgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, P.R. China.

Abstract

Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive neurological impairment. Asparagine endopeptidase (AEP), also known as legumain (LGMN), participates in multiple malignancies and neurodegenerative diseases and may potentially be involved in RIBI. Here, we found AEP expression was substantially elevated in the cortex and hippocampus of wild-type (Lgmn^+/+) mice following whole-brain irradiation. Lgmn knockout (Lgmn^-/-) alleviated neurological impairment caused by whole-brain irradiation by suppressing neuronal senescence. Bulk RNA and metabolomic sequencing revealed AEP's involvement in the antigen processing and presentation pathway and neuroinflammation. This was further confirmed by co-culturing Lgmn^+/+ primary neurons with the conditioned media derived from irradiated Lgmn^+/+ or Lgmn^-/- primary microglia. Furthermore, esomeprazole inhibited the enzymatic activity of AEP and RIBI. These findings identified AEP as a critical factor of neuroinflammation in RIBI, highlighting the prospect of targeting AEP as a therapeutic approach.

Keywords: Immunology; Metabolomics; Molecular biology; Neuroscience; Omics; Transcriptomics.