Per1/Per2 knockout Affects Spleen Immune Function in Elderly Mice via Inducing Spleen Lymphocyte Ferroptosis

Author:

He RuyiORCID,Zhang Shijie,Yu Jiale,Yu Xiaojie,Wang Jian,Qiu Yi,Zhou Wenting,Wang Fangyi,Ren Feng,Liu ZhiguoORCID

Abstract

Disturbances in circadian rhythms are known to affect immune functions. However, the long-term impact of abnormal circadian rhythms on the immune-related functions of the spleen are poorly understood. Hence, we aimed to investigate the immune-related functions of spleen in Per1/Per2 double-knockout (DKO) and wild-type (WT) mice aged 4, 9, and 14 months. Compared to the WT mice, the DKO mice had smaller spleen white pulp (WP) and lymphocyte germinal area, as well as fewer immune cells with age—these differences were especially clear. The spleen lymphocyte mortality, malondialdehyde (MDA) levels, reactive oxygen species (ROS) levels, and ferritin-binding receptor (TFR1) levels were significantly higher in the 14-month-old DKO mice than in WT mice of the same age. Transcriptome analysis showed that most of the differentially expressed mRNAs were enriched in DNA damage repair-related pathways. In DKO mice, spleen cells showed up-regulation of pro-ferroptosis genes, such as Cd36,Atm, and Acsl4, and down-regulation of anti-ferroptosis genes, such as GPX4. We found that long-term abnormalities in the circadian rhythm can induce DNA damage and ferroptosis in mouse spleen.

Funder

National Natural Science Foundation of China

Major Scientific and Technological Research Project of Tianjin

Central Government Guides Local Science and Technology Development Projects

State Key Laboratory of Biocatalysis and Enzyme Engineering Project

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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