ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression.
ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression.
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脓毒症、脓毒症诱导的炎症反应和随后的脓毒症相关免疫抑制（SAIS）是死亡的重要原因。在这里，我们表明，在人类的主要活性氧（ROS）清除剂，谷胱甘肽（GSH）的损失，在SAIS直接相关的转录激活因子3（ATF 3）的表达增加。在内毒素刺激的单核细胞中，ROS应激强烈超诱导NF-E2相关因子2（NRF 2）依赖性ATF 3。在体内，这种ROS介导的ATF 3超诱导通过抑制先天性细胞因子来保护免受内毒素休克，因为即使在ROS应激的条件下，Atf 3 −/−小鼠仍然对内毒素休克敏感。虽然它可以防止内毒素休克，但这种ROS介导的ATF 3超诱导通过抑制白细胞介素6（IL-6）引起对细菌和真菌感染的高度易感性。因此，Atf 3 −/−小鼠即使在ROS应激条件下也能免受细菌和真菌感染，而Atf 3 −/− Il 6 −/−小鼠对这些感染高度敏感。此外，在SAIS模型中，继发性感染导致Atf 3 −/−小鼠的死亡率比野生型小鼠低得多，表明ROS诱导的ATF 3在SAIS期间决定了继发性感染的易感性。
Sepsis, sepsis-induced hyperinflammation and subsequent sepsis-associated immunosuppression (SAIS) are important causes of death. Here we show in humans that the loss of the major reactive oxygen species (ROS) scavenger, glutathione (GSH), during SAIS directly correlates with an increase in the expression of activating transcription factor 3 (ATF3). In endotoxin-stimulated monocytes, ROS stress strongly superinduced NF-E2–related factor 2 (NRF2)–dependent ATF3. In vivo, this ROS-mediated superinduction of ATF3 protected against endotoxic shock by inhibiting innate cytokines, as Atf3−/− mice remained susceptible to endotoxic shock even under conditions of ROS stress. Although it protected against endotoxic shock, this ROS-mediated superinduction of ATF3 caused high susceptibility to bacterial and fungal infections through the suppression of interleukin 6 (IL-6). As a result, Atf3−/− mice were protected against bacterial and fungal infections, even under conditions of ROS stress, whereas Atf3−/−Il6−/− mice were highly susceptible to these infections. Moreover, in a model of SAIS, secondary infections caused considerably less mortality in Atf3−/− mice than in wild-type mice, indicating that ROS-induced ATF3 crucially determines susceptibility to secondary infections during SAIS.