Prostaglandin E2–Induced AKT Activation Regulates the Life Span of Short-Lived Plasma Cells by Attenuating IRE1α Hyperactivation

The mechanism regulating the life span of short-lived plasma cells (SLPCs) remains poorly understood. Here we demonstrated that the EP4-mediated activation of AKT by PGE2 was required for the proper control of inositol-requiring transmembrane kinase endoribonuclease-1α (IRE1α) hyperactivation and he...

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Published in:The Journal of immunology (1950) 2022-04, Vol.208 (8), p.1912-1923
Main Authors: Wang, Wei, Qin, Xiaodan, Lin, Liang, Wu, Jia, Sun, Xiuyuan, Zhao, Ye, Ju, Yurong, Zhao, Ziheng, Ren, Liwei, Pang, Xuewen, Guan, Youfei, Zhang, Yu
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Language:English
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Summary:The mechanism regulating the life span of short-lived plasma cells (SLPCs) remains poorly understood. Here we demonstrated that the EP4-mediated activation of AKT by PGE2 was required for the proper control of inositol-requiring transmembrane kinase endoribonuclease-1α (IRE1α) hyperactivation and hence the endoplasmic reticulum (ER) homeostasis in IgM-producing SLPCs. Disruption of the PGE2-EP4-AKT signaling pathway resulted in IRE1α-induced activation of JNK, leading to accelerated death of SLPCs. Consequently, Ptger4-deficient mice (C57BL/6) exhibited a markedly impaired IgM response to T-independent Ags and increased susceptibility to Streptococcus pneumoniae infection. This study reveals a highly selective impact of the PGE2-EP4 signal on the humoral immunity and provides a link between ER stress response and the life span of SLPCs.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.2100466