Inhibition of endoplasmic reticulum stress and the downstream pathways protects CD4⁺ T cells against apoptosis and immune dysregulation in sepsis

Abstract

Immunosuppression mediated by CD4 + T cell apoptosis and dysfunction is a key factor in promoting the progression of sepsis. Endoplasmic reticulum (ER) stress participates in the apoptosis and dysfunction of immune cells. We aimed to investigate the role of ER stress inhibition in CD4 + T cells in both in vitro and in vivo models of sepsis. In vitro model of sepsis was established with lipopolysaccharide (LPS) and the rat model of sepsis was established using cecal ligation and puncture (CLP). After the LPS treatment or CLP, ER stress inhibitors including 4-PBA, SNJ-1945, and SP600125 were used to treat cells or rats, and the CD4 + T cells were obtained by magnetic bead sorting. The effects of ER stress inhibitors on apoptosis and the function of CD4 + T cells were evaluated. After the LPS stimulation or CLP, the levels of ER stress and downstream markers (PERK, eIF2α, IRE-1α, ATF6, ATF4, XBP-1 s, GRP78, CHOP, and p-JNK) were increased in CD4 + T cells at the beginning of sepsis. Meanwhile, the number of apoptotic CD4 + T cells markedly increased. In addition, sepsis impaired the function of CD4 + T cells, manifested by the increased population of Th1, Th2, Th17, and Treg, as well as the production of TNF-α, interleukin (IL)-6, IL-4, and IL-10. However, inhibitors of ER stress, JNK, and calpain all decreased the induction of Th1 and Th17, enhanced the increase of Th2 and Treg, decreased the production of TNF-α and IL-6, and enhanced the production of IL-4 and IL-10. Our findings indicate that ER stress inhibitors may play a protective role by reducing CD4 + T cell apoptosis and maintaining CD4 + T cell function, which may be useful for enhancing the immune function and poor prognosis of patients with sepsis.

Yamogenin Exhibits Antidepressant-like Effects via Inhibition of ER Stress and Microglial Activation in LPS-Induced Mice

“…Moreover, excessive ER stress induced by LPS-induced inflammation was associated with accelerated apoptosis, characterized by decreased levels of the antiapoptotic protein Bcl-2 and increased levels of the proapoptotic protein caspase-3 . Conversely, inhibition of ER stress had a protective effect, reducing apoptosis . In line with these observations, our study demonstrated that yamogenin significantly inhibited the PERK/eIF2α/ATF4/CHOP signaling pathway in the prefrontal cortex of mice exhibiting depression-like behavior.…”

“…25 Conversely, inhibition of ER stress had a protective effect, reducing apoptosis. 26 In line with these observations, our study demonstrated that yamogenin significantly inhibited the PERK/eIF2α/ATF4/ CHOP signaling pathway in the prefrontal cortex of mice exhibiting depression-like behavior. Furthermore, yamogenin maintained the expression of the antiapoptotic protein Bcl-2 while reducing the levels of the proapoptotic protein caspase-3, providing further evidence of its potential as a neuroprotective agent.…”

The Role of XBP1 in bone metabolism

“…At the same time, apoptosis of CD4+ T cells was significantly increased. This phenomenon was improved with the application of ER stress inhibitors ( 83 ). In addition, measuring the expression of IRE1α mRNA and protein in differentiated and reactivated Th2 cells in vitro using qPCR and Western blot showed that the IRE1α/XBP1 pathway is upregulated during helper T cell activation in vitro .…”

Predicting the prognosis in patients with sepsis by an endoplasmic reticulum stress gene signature

“…Recognizing the role of ER stress in the pathology of sepsis is important [ 12 ]. Lu et al [ 13 ] found that inhibition of ER stress inhibits apoptosis and immune dysregulation in sepsis. Qian et al [ 14 ] showed that ER-related proteins are significantly expressed in the liver of rats with sepsis, and inhibition of endoplasmic reticulum stress can reduce liver cell apoptosis.…”