IL-1β/TNF-α/IL-6 inflammatory cytokines promote STAT1-dependent induction of CH25H in Zika virus–infected human macrophages

Abstract

Zika virus (ZIKV) 3 is an enveloped, single-stranded, positive-sense RNA virus of the Flaviviridae family that has emerged as a public health threat because of its global transmission and link to microcephaly. Currently there is no vaccine for this virus. Conversion of cholesterol to 25-hydroxycholesterol by cholesterol 25-hydroxylase (CH25H) has been shown to have broad antiviral properties. However, the molecular basis of induction of CH25H in humans is not known. Elucidation of signaling and transcriptional events for induction of CH25H expression is critical for designing therapeutic antiviral agents. In this study, we show that CH25H is induced by ZIKV infection or Toll-like receptor stimulation. Interestingly, CH25H is induced by pro-inflammatory cytokines, including IL-1␤, tumor necrosis factor ␣, and IL-6, and this induction depends on the STAT1 transcription factor. Additionally, we observed that cAMP-dependent transcription factor (ATF3) weakly binds to the CH25H promoter, suggesting cooperation with STAT1. However, ZIKV-induced CH25H was independent of type I interferon. These findings provide important information for understanding how the Zika virus induces innate inflammatory responses and promotes the expression of anti-viral CH25H protein.

RETRACTED ARTICLE: Exosomes-carried microRNA-26b-5p regulates microglia M1 polarization after cerebral ischemia/reperfusion

“…A previous research observed high CH25H expression in specifically vulnerable brain regions in patients with Alzheimer's disease [31]. Interestingly, CH25H was induced by proinflammatory cytokines IL-1β, TNF-α, and IL-6 [32]. As a hydroxylating enzyme, CH25H converts cholesterol into 25-hydroxycholesterol (25HC), which contributed to cerebral inflammation, and significantly recruited Iba-1-positive microglia, caused oligodendrocyte apoptosis, and amplified the production of pro-inflammatory and TLRinduced cytokines [33].…”

Glutaredoxin 1 regulates macrophage polarization through mediating glutathionylation of STAT1

“…6 Catalyzed by activated Janus tyrosine kinase (JAK), STAT is phosphorylated and forms activated dimers, which then enter the nucleus combining with targeted DNA motifs to regulate gene transcription and participate in a variety of physiological or pathological processes. 24 Considering that the phosphorylation of STAT1 occurs at the early stage after macrophages are appropriately stimulated, 25,26 we chose to test the levels of P-STAT1 at 0.5 hours/1 hour after stimulation. Many studies have clarified the relationship between oxidative stress and STAT1 in different aspects.…”

IP-10 and CXCR3 signaling inhibit Zika virus replication in human prostate cells

“…However, the direct role of IP-10 in ZIKV urogenital tract infection has yet to be studied. In addition, other studies in human macrophages have described the ability of ZIKV to upregulate pro-inflammatory cytokines that are responsible for induction of anti-viral proteins, such as CH25H [ 73 ]. However, one limitation of this study includes using PNT1a cells for assessing cytokine production.…”