Prostaglandin E₂-Induced AKT Activation Regulates the Life Span of Short-Lived Plasma Cells by Attenuating IRE1a 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-1a (IRE1a) hyperactivation and hence the endoplasmic reticulum (ER) homeostasis in IgM-producing SLPCs. Disruption of the PGE₂-EP4-AKT signaling pathway resulted in IRE1a-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 PGE₂EP4 signal on the humoral immunity and provides a link between ER stress response and the life span of SLPCs.