Work

The immune regulation and signaling transduction of FAM134B-mediated endoplasmic reticulum-phagy in ferroptosis of dendritic cells after sepsis

Year: 2025

Type: article

Abstract: • The receptor for ER-phagy named FAM134B reached up to a peak level when stimulated by LPS with a dosage of 1 μg/ml at 12 h. Dramatically, ER-phagy is substantially activated when confronting sepsis and contributes to relieve ER pressure and restore ER homeostasis. • Sepsis-induced ferroptosis resulted in a suppressive effect on the maturational function of dendritic cells. • FAM134B-mediated ER-phagy protected the immune function of dendritic cells by inhibiting ferroptosis. Consequently, ER-phagy upregulation is conductive to defenses against oxidative stress and ROS accumulation. • FAM134B-mediated ER-phagy is identified as a stress-defensive mechanism to maintain cellular survival, and ER-phagy defection has been confirmed to be related to septic pathologies. • FAM134B-mediated ER-phagy protected DCs against LPS-induced ferroptosis by up-regulation of ARF6-ACSL4 signaling pathway. Fam134B-mediated endoplasmic reticulum (ER)-phagy is one of the key mechanisms for maintaining functional homeostasis of ER and cell survival. In fact, Fam134B-mediated ER-phagy has been proved to exert a double-edged sword in response to inflammatory and oxidative stress, which is evidenced by the recovery effect on an appropriate organellar autophagy whereas the activation of cell death in excessive condition. However, its potential role and significance in regulating the immunoreaction within the framework of sepsis and its associated mechanisms remain to be elucidated. The present research aimed to explore the effects of FAM134B on mediating ER-phagy in DCs after sepsis. By use of DCs from FAM134B -/- mice stimulated with LPS in vitro and CLP-induced septic model in vivo with CD11c cre FAM134B fl/fl mice, the impact of FAM134B-mediated ER-phagy on ferroptosis and immune function of DCs will be analyzed adequately. Moreover, interventions targeted on the signaling molecular of ARF6, which locates on organelle plasma membrane, will be further employed to clarify the main signaling transduction in ferroptosis of DCs. The upregulation of FAM134B upon septic challenge could exert a protective impact on ferroptosis and immune function of dendritic cells (DCs). FAM134B −mediated ER-phagy was activated in DCs stimulated by LPS (1 μg/ml) at the peak time of 12 h, which presented a parallel impact on DCs. DCs in genetic knockout mice for FAM134B (FAM134B -/- ) showed an enhanced ferroptosis. Additionally, the protect effect of FAM134B on ferroptosis was proved to be related to ARF6 upregulation, eventually preventing from lipid peroxidation of plasmalemma. This study demonstrated the intrinsic connection between FAM134B −mediated ER-phagy, ferroptosis, as well as sepsis-induced immune dysfunction, which might provide new targeted strategies for immune modulation in septic complications.

Source: Journal of Advanced Research

DOI: 10.1016/j.jare.2025.07.058