TLR4-Mediated Pathway Triggers Interferon-Independent G0 Arrest and Antiviral SAMHD1 Activity in Macrophages

• Published in: Cell reports (Cambridge) 2020-03, Vol.30 (12), p.3972-3980.e5
• Main Authors: Mlcochova, Petra, Winstone, Helena, Zuliani-Alvarez, Lorena, Gupta, Ravindra K.
• Format: Article
• Language: English
• Subjects: Antiviral Agents - metabolism; Cell Cycle Checkpoints - drug effects; cell-cycle arrest; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Escherichia coli - metabolism; E Coli; Female; HIV; HIV Infections - pathology; human macrophages; Humans; interferon; Interferons - metabolism; Lipopolysaccharides - pharmacology; LPS; Macrophages - metabolism; Macrophages - virology; Male; Myeloid Differentiation Factor 88 - metabolism; Resting Phase, Cell Cycle - drug effects; SAM Domain and HD Domain-Containing Protein 1 - metabolism; SAMHD1; Signal Transduction - drug effects; TLR4; Toll-Like Receptor 4 - metabolism; Toll-Like Receptor 5 - metabolism; Up-Regulation - drug effects
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.03.008

Macrophages exist predominantly in two distinct states, G0 and a G1-like state that is accompanied by phosphorylation of SAMHD1 at T592. Here, we demonstrate that Toll-like receptor 4 (TLR4) activation can potently induce G0 arrest and SAMHD1 antiretroviral activity by an interferon (IFN)-independent pathway. This pathway requires TLR4 engagement with TRIF, but not involvement of TBK1 or IRF3. Exclusive Myd88 activators are unable to trigger G0 arrest or SAMHD1 dephosphorylation, demonstrating this arrest is also Myd88/nuclear factor κB (NF-κB) independent. The G0 arrest is accompanied by p21 upregulation and CDK1 depletion, consistent with the observed SAMHD1 dephosphorylation at T592. Furthermore, we show by SAMHD1 knockdown that the TLR4-activated pathway potently blocks HIV-1 infection in macrophages specifically via SAMHD1. Together, these data demonstrate that macrophages can mobilize an intrinsic cell arrest and anti-viral state by activating TLR4 prior to IFN secretion, thereby highlighting the importance of cell-cycle regulation as a response to pathogen-associated danger signals in macrophages. [Display omitted] •TLR4 activation mediates TRIF-dependent G0 arrest in human primary macrophages•G0 arrest regulates phosphorylation and antiretroviral activity of SAMHD1•SAMHD1 is responsible for the IFN-independent HIV-1 blockade after TLR4 activation•Whole gram-negative bacteria induce IFN-independent G0 arrest in human MDMs Mlcochova et al. demonstrate that TLR4 activation regulates the cell cycle in human primary macrophages. This culminates in G0 arrest and activation of the antiviral protein SAMHD1, suggesting that macrophages can achieve a heightened state of alert in response to pathogen-associated danger signals in macrophages prior to type I IFN secretion.