Sestrin2 protects dendrite cells against ferroptosis induced by sepsis

Abstract

Ferroptosis is a nonapoptotic form of programmed cell death triggered by the accumulation of reactive oxygen species (ROS) depended on iron overload. Although most investigations focus on the relationship between ferroptosis and cancer, neurodegenerative diseases, and ischemia/reperfusion injury, research on ferroptosis induced by immune-related inflammatory diseases, especially sepsis, is scarce. Sestrin2 (Sesn2), a highly evolutionary and stress-responsive protein, is critically involved in defense against oxidative stress challenges. Upregulated expression of Sesn2 has been observed in preliminary experiments to have an antioxidative function in the context of an inflammatory response. Nevertheless, the underlying function of Sesn2 in inflammation-mediated ferroptosis in the immune system remains uncertain. The current study aimed to demonstrate the protective effect of Sesn2 on ferroptosis and even correlations with ferroptosis and the functions of ferroptotic-dendritic cells (DCs) stimulated with lipopolysaccharide (LPS). The mechanism underlying DCs protection from LPS-induced ferroptosis by Sesn2 was further explored in this study. We found that the immune response of DCs assessed by co-stimulatory phenotypes was gradually enhanced at the peak time of 12 h upon 1 μg/ml LPS stimulation while ferroptosis in DCs treated with LPS at 24 h was significantly detected. LPS-induced ferroptosis showed a suppressive impact on DCs in phenotypic maturation, which was conversely relieved by the ferroptotic inhibitor. Compared with wild-type (WT) mice, DCs in genetic defective mice of Sesn2 (Sesn2−/−) exhibited exacerbated ferroptosis. Furthermore, the protective effect of Sesn2 on ferroptosis was noticed to be associated with the ATF4-CHOP-CHAC1 pathway, eventually exacerbating ferroptosis by degrading of glutathione. These results indicate that Sesn2 can suppress the ferroptosis of DCs in sepsis by downregulating the ATF4-CHOP-CHAC1 signaling pathway, and it might play an antioxidative role.

Ferroptosis: A Critical Moderator in the Life Cycle of Immune Cells

“…In the late stage of sepsis, macrophages will release high mobility group protein B1 (HMGB1), which can stimulate the expression of Sesn2 in DCs ( 82 ). Sesn2 inhibits the ferroptosis of DCs in sepsis by down-regulating the ATF4-CHOP-CHAC1 signaling pathway and exerts an antioxidant effect ( 83 ). This discovery inspires us that exploring the relationship between sepsis and ferroptosis may help us overcome sepsis, a disease that seriously threatens human health.…”

Vitamin B6 Alleviates Lipopolysaccharide-induced Myocardial Injury by Ferroptosis and Apoptosis Regulation

“…Ferroptosis is iron-dependent and characterized by the accumulation of intracellular ROS and lipid peroxidation products (Dixon et al, 2012;Li et al, 2021). To explore the influences of LPS and VitB6 on non-heme iron, we measured iron levels in serum and myocardial tissue.…”

“…Ferroptosis comprehends a new cell death type, distinct from apoptosis, necrosis, and autophagy in genetical, biochemical, and morphological aspects (Dixon et al, 2012). This iron-dependent cell death type is characterized by the accumulation of intracellular reactive oxygen species (ROS) and lipid peroxidation products (Dixon et al, 2012;Li et al, 2021). Many researchers demonstrated that ferroptosis can be related to multiple diseases, such as ischemia-reperfusion (I/R)-induced cardiomyopathy (Fang et al, 2019), kidney degeneration, neurodegenerative diseases (Stockwell et al, 2017), and various cancers.…”

LPIN1 Is a Regulatory Factor Associated With Immune Response and Inflammation in Sepsis

“…Ferroptosis was firstly identified by Dolma et al (7) in cancer cells and was found to be different from apoptosis, pyroptosis, and necroptosis, which are also involved in neurotoxicity, kidney injury, liver injury, and heart disease (8)(9)(10). Due to its role in multiple organs, ferroptosis has also been implicated in sepsis (11). However, the genetic background of ferroptosis in sepsis remains elusive.…”