Abstract
Succinate is at the crossroads of multiple metabolic pathways and plays a role in several immune responses acting as an inflammation signal. However, whether succinate regulates antiviral immune response remains unclear. Here, we found that the production of succinate was reduced in RAW264.7 cells during vesicular stomatitis virus (VSV) infection. Using diethyl succinate to pretreat the mouse peritoneal macrophages and RAW264.7 cells before VSV infection, the production of interferon-β (IFN-β), chemokine (C–X–C motif) ligand 10 (CXCL-10), and IFN-stimulated genes 15 (ISG15) was significantly decreased, following which the VSV replication in diethyl succinate-pretreated cells was obviously increased. Moreover, succinate decreased the expression of IFN-β in serum, lung, and spleen derived from the VSV-infected mice. The overall survival rate in the VSV-infected mice with diethyl succinate pretreatment was also remarkably downregulated. Furthermore, we identified that succinate inhibited the activation of MAVS-TBK1-IRF3 signaling by suppressing the formation of MAVS aggregates. Our findings provide previously unrecognized roles of succinate in antiviral immune response and establish a novel link between metabolism and innate immune response.
Highlights
Cellular metabolism is considered a prominent route in our quest to understand immune responses [1]
RT-qPCR analysis showed that the mRNA levels of glucose transporter (GLUT) 1 and GLUT4 were significantly increased in the RAW264.7 cells and mouse peritoneal macrophages (MPM) infected with vesicular stomatitis virus (VSV) for 12 h, while there were no changes in the PBS-treated group (Figures 1A, B)
The mRNA levels of tricarboxylic acid (TCA) cycle key enzymes isocitrate dehydrogenase 1 (IDH1) and a-ketoglutarate dehydrogenase (OGDH) in RAW264.7 cells and MPM were gradually decreased with the prolongation of VSV infection time (Figures 1C, dimethyl succinate (Ds))
Summary
Cellular metabolism is considered a prominent route in our quest to understand immune responses [1]. The Krebs cycle metabolite succinate has been in succession reported that concerned with immune responses. Succinate could induce migratory responses of dendritic cells and act in synergy with Toll-like receptor ligands for proinflammatory cytokine production. Succinate Suppresses Antiviral Immune Response through binding to succinate receptor SUNCR1, known as G protein–coupled receptor (GPR91) [2]. SUNCR1 is expressed on various types of cells including immune cells [3]. Via the succinate-SUNCR1 signaling axis, succinate triggered proinflammatory response in macrophages during antigeninduced arthritis and induced a type 2 immune response in the small intestine [4–6]. In the lipopolysaccharide (LPS)-stimulated macrophages, succinate acted as a metabolite in innate immune signaling to enhance interleukin-1b production through hypoxia-inducible factor-1a [7]. Whether succinate has a role in antiviral immune response remains unclear
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