Frontline Science: ATF3 is responsible for the inhibition of TNF‐α release and the impaired migration of acute ethanol‐exposed monocytes and macrophages

Acute ethanol exposure decreases the production of LPS‐induced TNF‐α, and the migration of monocytes and macrophages via ATF3. Binge drinking represses host innate immunity and leads to a high risk of infection. Acute EtOH‐pretreated macrophages exhibit a decreased production of proinflammatory mediators in response to LPS. ATF3 is induced and counter‐regulates the LPS/TLR4 inflammatory cascade. Here, we investigated the potential role of ATF3 in LPS tolerance in acute ethanol‐pretreated macrophages. We found that there was an inverse correlation between ATF3 and LPS‐induced TNF‐α production in acute ethanol‐pretreated murine monocytes and macrophages. The knockdown of ATF3 attenuated the inhibitory effects of acute ethanol treatment on LPS‐induced TNF‐α production. Furthermore, ChIP assays and co‐IP demonstrated that ATF3, together with HDAC1, negatively modulated the transcription of TNF‐α. In binge‐drinking mice challenged with LPS, an up‐regulation of ATF3 and HDAC1 and a concomitant decrease in TNF‐α were observed. Given that HDAC1 was concomitantly induced in acute ethanol‐exposed monocytes and macrophages, we used the HDACi TSA or silenced HDAC1 to explore the role of HDAC1 in acute ethanol‐treated macrophages. Our results revealed that TSA treatment and HDAC1 knockdown prevented acute ethanol‐induced ATF3 expression and the inhibition of TNF‐α transcription. These data indicated a dual role for HDAC1 in acute ethanol‐induced LPS tolerance. Furthermore, we showed that the induction of ATF3 led to the impaired migration of BM monocytes and macrophages. Overall, we present a novel role for ATF3 in the inhibition of LPS‐induced TNF‐α and in the impairment of monocyte and macrophage migration.