A novel TLR 4 mediated pathway triggers interferon independent G0 arrest and 2 antiviral SAMHD1 activity in macrophages
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Mlcochova, P., Winstone, H., Zuliani-Alvarez, L., & Gupta, R. A novel TLR 4 mediated pathway triggers interferon independent G0 arrest and 2 antiviral SAMHD1 activity in macrophages. Cell Reports https://doi.org/10.17863/CAM.49548
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 TLR4 activation mediated by LPS or ingestion of whole E. Coli can potently induce G0 arrest and SAMHD1 antiretroviral activity by a novel IFN-independent pathway. This pathway is not sensitive to TBK1 depletion or to block of IRF3 translocation, but is sensitive to TRIF depletion by siRNA, indicating that the pathway requires TLR4 engagement with TRIF but not involvement of TBK1 dependent IRF3 translocation. Exclusive Myd88 activators, such as Tenascin C, a product of tissue breakdown that activates TLR4, and Flagellin, a bacterial protein recognized by TLR5, are unable to trigger G0 arrest or SAMHD1 dephosphorylation, demonstrating this arrest is also Myd88- and thus NFkB-independent. The G0 arrest is accompanied by p21 upregulation and CDK1 depletion, consistent with the observed SAMHD1 dephosphorylation at T592. Furthermore, we show by siRNA knockdown of SAMHD1 that this TLR4 activated pathway is able to potently block 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.
Wellcome Trust (108082/A/15/Z)
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This record's DOI: https://doi.org/10.17863/CAM.49548
This record's URL: https://www.repository.cam.ac.uk/handle/1810/302480