Notch Signaling Pathway Was Involved in Regulating Programmed Cell Death 1 Expression during Sepsis‐Induced Immunosuppression

Abstract

Programmed cell death 1 (PD-1) plays an important pathologic role in sepsis-induced immunosuppression. However, whether PD-1 overexpression occurs early during septic shock is unknown and its regulation mechanism is also unknown. Our study investigated the expressions of PD-1/programmed death-ligand 1 (PD-L1) on immune cells in peripheral blood from the early-stage septic shock patients. We found that both PD-1 and PD-L1 showed increased expressions on the CD4+ T cells and monocytes. It indicated that PD-1 expression might be an early biomarker to assess illness severity and predict the prognosis of septic shock. Then, we further investigated the mechanism underlying the regulation of PD-1 expression. Our data showed that Notch signaling pathway was activated in both septic shock patients and lipopolysaccharide- (LPS-) tolerant THP1 cells and both interleukin-10 (IL-10) and PD-1 were increased in the THP1 cells. Inhibition of Notch signaling by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenyl glycinet-butyl ester (DAPT) induced significantly decreased expressions of PD-1 and IL-10 in the LPS-tolerant cell model. Our work suggested that Notch signaling pathway was involved in the regulation of PD-1 expression.

Jagged1‐expressing adenovirus‐infected dendritic cells induce expansion of Foxp3+ regulatory T cells and alleviate T helper type 2‐mediated allergic asthma in mice

“…Importantly, by inhibiting the Notch signaling pathway in a lipopolysaccharide‐tolerant THP1 cell model, Pan et al . found that the Notch signaling pathway was involved in up‐regulating PD‐L1 expression in monocytes . On the other hand, the role of OX40L in the induction of Treg cells is controversial.…”

“…17 Importantly, by inhibiting the Notch signaling pathway in a lipopolysaccharide-tolerant THP1 cell model, Pan et al found that the Notch signaling pathway was involved in up-regulating PD-L1 expression in monocytes. 48 On the other hand, the role of OX40L in the induction of Treg cells is controversial. Although a study by Gopisetty et al demonstrated that OX40L-and Jagged1-induced co-signaling by BMDCs was required for Treg cell expansion, 25 most reports supported up-regulation of OX40L on DCs being implicated in the induction of Th2 responses and allergic asthma.…”

Genetic and Epigenetic Regulation of PD-1 Expression

“…Corroborating this, the Notch intracellular domain and the recombination signal binding protein for immunoglobulin kappa J (RBPJκ), two critical components of the Notch signaling pathway, were bound to the Pdcd1 locus within six hours of in vitro peptide-mediated TCR stimulation (Figure 1b). Similarly, in T cells of patients experiencing sepsis-induced immunosuppression, Notch pathway activation also correlated with PD-1 expression (74). In a model using IL-10 and LPS to cause sepsis-induced immunosuppression in CD4 T cells and macrophages, inhibition of Notch signaling again reduced PD-1 expression.…”

PD-L1 is overexpressed on breast cancer stem cells through notch3/mTOR axis

“…Similar relationship between Notch pathway and PD-1, a receptor for PD-L1 on lymphocytes, has been reported previously in septic shock patients, where inhibition of Notch pathway significantly decreased PD-1 expressions. 27 Moreover, it has been shown that Notch is required for PD-1 upregulation during CD8 + T-cell activation. 28 Likewise, PD-L1 was upregulated through a notch in human primary monocytes.…”