Formyl peptide receptor 2 is regulated by RNA mimics and viruses through an IFN-b-STAT3-dependent pathway

Abstract

© FASEB. The regulation of host factors is a key strategy employed by viruses to suppress host defense systems and enhance their propagation; however, the mechanisms that underlie this regulation is still unclear. Formyl peptide receptor 2 (FPR2) recognizes numerous proinflammatory and anti-inflammatory stimuli, and emerging reports indicate elevatedlevels of FPR2 in several disease conditions.Although studieshave implicated FPR2 ina myriad of inflammatory conditions, how viruses exploit this cell-surface receptor to facilitate disease progression remains unknown. In this study, we show that the activation of TLR3 and TLR7 induces the up-regulation of FPR2. We provide evidence that signal transducer and activator of transcription 3 (STAT3) phosphorylation is critical for the induction of FPR2 by double-stranded RNA, but not single-stranded RNA viral mimetics. Use of bone marrow- derived macrophages (BMDMs) from IFN-αβ receptor-deficient mice revealed that signaling via the type I IFNSTAT3 pathway is essential for FPR2 induction.Wedemonstrate that virus infectionwith enterovirus 71 andH1N1 PR8 influenza virus results in increased FPR2 expression. Inhibition of STAT3 phosphorylation in virus-infected cells repressed the induction of FPR2, which led to a reduction in viral loads. Finally, the absence of FPR2 inmurine BMDMs resulted in lower viral loads, which suggests that FPR2may be important for virus replication.Altogether, our study provides novel insights intohowRNAvirusesmay hijackthe immune systemto facilitate their replication and survival. Identification of these regulatory elementsmay be useful in designing therapeutics for inflammatory disease conditions that are associatedwith elevated levels of FPR2.