Hyperexpression of tumor necrosis factor receptor 2 inhibits differentiation of myeloid‐derived suppressor cells by instigating apolarity during ageing
Ming Wang,
Yijie Han,
Xiaohan Yao,
Xixi Duan,
Jiajia Wan,
Xiaohan Lou,
Yan Yan,
Peiguo Zheng,
Fazhan Wang,
Linyu Zhu,
Chen Ni,
Zhenzhen Pan,
Zihao Wang,
Lin Chen,
Zhaoqing Wang,
Zhihai Qin
Affiliations
Ming Wang
Medical Research Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou Henan China
Yijie Han
Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics Chinese Academy of Sciences Beijing China
Xiaohan Yao
Medical Research Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou Henan China
Xixi Duan
Medical Research Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou Henan China
Jiajia Wan
Medical Research Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou Henan China
Xiaohan Lou
Medical Research Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou Henan China
Yan Yan
Medical Research Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou Henan China
Peiguo Zheng
Clinical Laboratory the First Affiliated Hospital of Zhengzhou University Zhengzhou Henan China
Fazhan Wang
Medical Research Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou Henan China
Linyu Zhu
Medical Research Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou Henan China
Chen Ni
Medical Research Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou Henan China
Zhenzhen Pan
Medical Research Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou Henan China
Zihao Wang
Medical Research Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou Henan China
Lin Chen
Medical Research Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou Henan China
Zhaoqing Wang
Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics Chinese Academy of Sciences Beijing China
Zhihai Qin
Medical Research Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou Henan China
Abstract During the ageing process, TNF‐α can promote the expansion of myeloid‐derived suppressor cells (MDSCs). However, it remains unclear which receptor(s) of TNF‐α are involved in and how they modulate this process. Here, we report that TNFR2 hyperexpression induced by either TNF‐α or IL‐6, two proinflammatory factors of senescence‐associated secretory phenotype (SASP), causes cellular apolarity and differentiation inhibition in aged MDSCs. Ex vivo overexpression of TNFR2 in young MDSCs inhibited their polarity and differentiation, whereas in vivo depletion of Tnfr2 in aged MDSCs promotes their differentiation. Consequently, the age‐dependent increase of TNFR2 versus unaltered TNFR1 expression in aged MDSCs significantly shifts the balance of TNF‐α signaling toward the TNFR2–JNK axis, which accounts for JNK‐induced impairment of cell polarity and differentiation failure of aged MDSCs. Consistently, inhibiting JNK attenuates apolarity and partially restores the differentiation capacity of aged MDSCs, suggesting that upregulated TNFR2/JNK signaling is a key factor limiting MDSC differentiation during organismal ageing. Therefore, abnormal hyperexpression of TNFR2 represents a general mechanism by which extrinsic SASP signals disrupt intrinsic cell polarity behavior, thereby arresting mature differentiation of MDSCs with ageing, suggesting that TNFR2 could be a potential therapeutic target for intervention of ageing through rejuvenation of aged MDSCs.
