The endoplasmic reticulum(ER)is an essential organelle that maintains intracellular Ca2+homeostasis,folds newly synthesized secreted and membrane proteins,and facilitates post-translational protein modifications.Misfolding and aggregation of unfolded proteins within the ER lumen can activate endoplasmic reticulum stress(ERS),which in turn activates three different downstream signaling pathways:protein kinase R-like endoplasmic reticulum kinase(PERK),inositol-requiring enzyme 1α(IRE11α),and activating transcription factor6(ATF6).These pathways affect cell survival,differentiation,and phenotype transition.Recent studies have shown a close interaction between the downstream signaling cascade of ERS and the signaling pathways that induce macrophage polarization towards pro-inflammatory M1 type(IFN-γ and LPS)and anti-inflammatory M2 type(IL-4 and IL-10).However,the specific molecular mechanisms underlying these interactions are complex and intriate.The article summarizes the primary mechanisms by which ERS mediates macrophage polarization,focusing on discussing the molecular mechanisms by which three different downstream signals of ERS affect macrophage polarization.
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