Peli1 negatively regulates type I interferon induction and antiviral immunity in the CNS.

Yichuan Xiao,Xuhong Cheng,Jin Jin,Hongbo Hu,Shao-Cong Sun,Qiang Zou

doi:10.1186/s13578-015-0024-z

Abstract

BackgroundType I interferons (IFN-Is) serve as mediators of antiviral innate immunity and also regulate adaptive immune responses. The molecular mechanism that regulates virus-induced IFN-I production, particularly in tissue-resident immune cells, is incompletely understood.ResultsHere we identified the E3 ubiquitin ligase Peli1 as a negative regulator of IFN-I induction in microglia, innate immune cells of the central nervous system (CNS). Peli1 deficiency profoundly promoted IFN-β expression in microglia in response to in vitro stimulation by toll-like receptor (TLR) ligands or a CNS-tropic virus, the vascular stomatitis virus (VSV). Upon intranasal infection with VSV, the Peli1-deficient mice displayed heightened in vivo IFN-I responses in the CNS, coupled with reduced brain viral titer and increased survival rate.ConclusionsThese results establish Peli1 as an innate immune regulator in the CNS that modulates the threshold of IFN-I responses against viral infections.

Highlights

Type I interferons (IFN-Is) serve as mediators of antiviral innate immunity and regulate adaptive immune responses
Peli1 negatively regulates toll-like receptor (TLR)-mediated IFN-β induction in microglia To investigate the role of Peli1 in regulating IFN-I induction, we prepared primary BMDM and microglia from Peli1-KO mice and wildtype (WT) control mice
As we previously reported [14], the Peli1 deficiency in microglia profoundly inhibited the induction of several proinflammatory cytokines by LPS and other TLR ligands (Fig. 1b, c)

Summary

Introduction

Type I interferons (IFN-Is) serve as mediators of antiviral innate immunity and regulate adaptive immune responses. The molecular mechanism that regulates virus-induced IFN-I production, in tissue-resident immune cells, is incompletely understood. Type I interferons (IFN-Is) provide one of the body’s primary defense systems against viral infections. The high susceptibility of type I IFN receptor (IFNAR)-deficient mice to infection by a variety of viruses provides strong evidence for the major role of the IFN system in antiviral innate immunity [1]. Induction of IFN-Is is mediated by pattern-recognition receptors (PRRs), such as the toll-like receptors (TLRs) and the cytoplasmic RIG-I-like receptors (RLRs). The PRRs can efficiently detect viral infections through recognition of molecular patterns associated with viral genomes and replication products [3,4,5]. The TRIF-dependent TLRs, TLR3 and TLR4, as well as the RLRs stimulate Ifnb gene expression via activation of two homologous kinases, TBK1 and IKKε

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