Acetylation-Dependent Regulation of Notch Signaling in Macrophages by SIRT1 Affects Sepsis Development.

Xiaozhi Bai,Fu Han,Xiaoqiang Li,Julei Zhang,Jihong Shi,Yijie Zhang,Dahai Hu,Kejia Wang,Ting He,Yang Liu,Weixia Cai,Wei Zhang

doi:10.3389/fimmu.2018.00762

Xiaozhi Bai, Fu Han + Show 10 more

Open Access

https://doi.org/10.3389/fimmu.2018.00762

Copy DOI

Abstract

SIRT1 is reported to participate in macrophage differentiation and affect sepsis, and Notch signaling is widely reported to influence inflammation and macrophage activation. However, the specific mechanisms through which SIRT1 regulates sepsis and the relationship between SIRT1 and Notch signaling remain poorly elucidated. In this study, we found that SIRT1 levels were decreased in sepsis both in vitro and in vivo and that SIRT1 regulation of Notch signaling affected inflammation. In lipopolysaccharide (LPS)-induced sepsis, the levels of Notch signaling molecules, including Notch1, Notch2, Hes1, and intracellular domain of Notch (NICD), were increased. However, NICD could be deacetylated by SIRT1, and this led to the suppression of Notch signaling. Notably, in macrophages from myeloid-specific RBP-J−/− mice, in which Notch signaling is inhibited, pro-inflammatory cytokines were expressed at lower levels than in macrophages from wild-type littermates and in RBP-J−/− macrophages, and the NF-κB pathway was also inhibited. Accordingly, in the case of RBP-J−/− mice, LPS-induced inflammation and mortality were lower than in wild-type mice. Our results indicate that SIRT1 inhibits Notch signaling through NICD deacetylation and thus ultimately alleviates sepsis.

Highlights

Sepsis is a life-threatening condition caused by uncontrolled immune response triggered by infections [1, 2]
Because SIRT1 levels were altered during sepsis as mentioned earlier, we sought to determine whether changes in SIRT1 levels affect the expression of pro-inflammatory cytokines
When macrophages were treated with both LPS and SRT1720, an activator of SIRT1 [39], the activation of SIRT1 was accompanied with a downregulation of pro-inflammatory cytokines as compared with their expression in cells treated with LPS alone (Figure 2A)

Summary

Introduction

Sepsis is a life-threatening condition caused by uncontrolled immune response triggered by infections [1, 2]. Our understanding of sepsis has increased substantially in recent years, sepsis is still reported to be the leading cause of death in seriously ill patients, and the incidence of sepsis has been increasing every year [3, 4]. In both the initiation and the resolution of immune responses, macrophages function as crucial coordinators [5], and the polarization of macrophages, which are involved in the process of sepsis, is influenced by the microenvironment. For investigating the mechanism of sepsis, the LPS-induced inflammation model is extensively used [11, 12]

Methods

Results

Conclusion