CCR5-Dependent Activation of mTORC1 Regulates Translation of Inducible NO Synthase and COX-2 during Encephalomyocarditis Virus Infection

Abstract

Encephalomyocarditis virus (EMCV) infection of macrophages results in the expression of a number of inflammatory and anti-viral genes including inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2. EMCV-induced macrophage activation has been shown to require the presence of CCR5 and the activation of phosphoinositide-3 kinase (PI3K)-dependent signaling cascades. The purpose of this study was to determine the role of PI3K in regulating the macrophage responses to EMCV. We show that PI3K regulates EMCV-stimulated iNOS and COX-2 expression by two independent mechanisms. In response to EMCV infection, Akt is activated and regulates the translation of iNOS and COX-2 through the mTORC1 complex. The activation of mTORC1 during EMCV infection is CCR5-dependent and appears to function in a manner that promotes the translation of iNOS and COX-2. CCR5-dependent mTORC1 activation functions as an antiviral response, as mTORC1 inhibition increases the expression of EMCV polymerase. PI3K also regulates the transcriptional induction of iNOS and COX-2 in response to EMCV infection by a mechanism that is independent of Akt and mTORC1 regulation. These findings indicate that macrophage expression of the inflammatory genes iNOS and COX-2 occurs via PI3K- and Akt-dependent translational control of mTORC1 and PI3K-dependent, Akt-independent transcriptional control.

STAT3 Differentially Regulates TLR4-Mediated Inflammatory Responses in Early or Late Phases

“…In our study, we found that STAT3KO macrophages display strikingly upregulated levels of phosphorylated Akt and Lyn and increased mRNA levels of iNOS and COX-2 in early time points of LPS stimulation ( Figure 2 ). Relevant role of Akt in regulation of iNOS and COX-2 mRNA in STAT3KO macrophages was also elucidated using pharmacological inhibitors which are known to inhibit Akt activity in macrophages [ 57 , 88 , 89 ]. Treatment with BN82002 [ 57 ] and LY294002 [ 90 ] inhibited the mRNA expression of iNOS and COX-2 in STATKO cells stimulated with LPS for 1 h ( Figure 2 h).…”

Beyond HIV infection: Neglected and varied impacts of CCR5 and CCR5Δ32 on viral diseases

“…Some studies suggest that CCR5 influences different aspects of the pathogenesis of viruses belonging to the Picornaviridae family, including Encephalomyocarditis virus (Christmann et al, 2011;Shaheen et al, 2015), Coxsackievirus B3 (Valaperti et al, 2013), and Rhinovirus (Muehling et al, 2018), once CCR5 participates in the regulation of the host immune response during infection by these viruses. Considering the effects of the genetic variant CCR5Δ32 on CCR5 expression and CCR5-related immune responses, it is possible that CCR5Δ32 also shows some impact on EV-related diseases.…”

Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape

“…From what has been observed for HCV and G. duodenalis, it is possible that this stress response also regulates innate immune cell function. Additionally, mTOR has been shown to increase iNOS translation in RAW264.7, peritoneal macrophages, and GM-DCs [86,87]. Therefore, it is conceivable that mTOR inhibition because of pathogen-driven depletion of L-arginine, leads to a reduced iNOS expression which further limits NO production.…”