ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression

Abstract

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.

Novel Regulatory Action of Ribosomal Inactivation on Epithelial Nod2-Linked Proinflammatory Signals in Two Convergent ATF3-Associated Pathways

“…Although the mechanisms of two pathways for ATF3 downstream regulation in Nod2-activated proinflammatory signal could be different, ATF3 has been found to be an integral signaling molecule that regulates proinflammatory responses triggered by Nod2 activation in the current study as well as TLR activation (by bacterial endotoxins, circulating free fatty acids, reactive oxygen species, high-fat diet, and ischemia reperfusion injury) in previous investigations (14,40,41,74). Therefore, reagents that can modulate ATF3 expression could exert potent anti-inflammatory effects with a broad spectrum, but intervening specific signaling patterns in ATF3 downstream would be required for more delicate therapy in each pathogenic event.…”

“…activation by bacterial infection, ischemia-reperfusion injury, or stress-induced inflammatory responses (13,40,41). These previous studies have indicated that ATF regulates NF-kB expression through epigenetic or transcriptional mechanisms (13,14).…”

“…Whereas chronic induction of ATF3 expression by ribosomal inactivation can offer protection against inflammatory insults, ATF3 increases susceptibility to secondary infections during sepsis-associated immune suppression (40). The precise effects of ribosomal inactivation on the human immune system remain unknown, but both up-and downregulation of systemic and mucosal immune responses have been observed in different animal experiments (54-59).…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…ATF3 decreases IFN responses by controlling basal and inducible levels of IFN-β and expression of IFN target genes in macrophages (Labzin et al 2015). Thus, Atf3 −/− mice are more susceptible to endotoxic shock due to excessive cytokine production (Hoetzenecker et al 2012). ATF3 also mediates high-density lipoprotein (HDL)-induced anti-inflammatory reprogramming of macrophages by transcriptional repression of inflammatory genes (De Nardo et al 2014).…”

Immune Responsive Gene 1 (IRG1) Promotes Endotoxin Tolerance by Increasing A20 Expression in Macrophages through Reactive Oxygen Species

“…The studies showed that endotoxin tolerance reprograms TLR4 signaling with decreased proinflammatory cytokine production but increased anti-proinflammatory cytokine production by decreasing TLR4 expression, blocking tyrosine phosphorylation of TLR4 and TIRAP, TLR4-MyD88, and IRAK1-MyD88 assemblies, attenuating activation of IRAK4 and IRAK1, inhibiting K63-linked ubiquitination of IRAK1 and TRAF6, or increasing expression of negative regulators IRAK-M, SHIP-1, suppressor of cytokine signaling 1 (SOCS1), and A20 (13, 16 -18). Recently, ROS-induced ATF3 expression and TNF-activated GSK3 were found to be related with SAIS by mediating chromatin remodeling (19,20). However, the molecular mechanisms for endotoxin tolerance such as identification of epigenetic regulation needs to be further investigated.…”