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.

巨噬细胞主要以两种不同的状态存在，G0 和类似 G1 的状态，并伴有 SAMHD1 在 T592 处的磷酸化。在这里，我们证明 Toll 样受体 4 (TLR4) 激活可以通过干扰素 (IFN) 独立途径有效诱导 G0 期停滞和 SAMHD1 抗逆转录病毒活性。该通路需要 TLR4 与 TRIF 结合，但不涉及 TBK1 或 IRF3。独有的 Myd88 激活剂无法触发 G0 停滞或 SAMHD1 去磷酸化，表明这种停滞也是 Myd88/核因子 κB (NF-κB) 独立的。 G0 停滞伴随着 p21 上调和 CDK1 耗竭，与在 T592 观察到的 SAMHD1 去磷酸化一致。此外，我们通过 SAMHD1 敲低表明，TLR4 激活途径可有效阻断巨噬细胞中的 HIV-1 感染，特别是通过 SAMHD1。总之，这些数据表明巨噬细胞可以通过在 IFN 分泌之前激活 TLR4 来调动内在的细胞停滞和抗病毒状态，从而突出了细胞周期调节作为巨噬细胞中病原体相关危险信号的反应的重要性。