Biochemical and Biophysical Research Communications
Thioredoxin-2 impacts the inflammatory response via suppression of NF-κB and MAPK signaling in sepsis shock
Introduction
Sepsis, a complex syndromeprimarily following bacterial infection, is frequently associated with dysregulation of systemic inflammation, dysfunction of multiple organs and coagulation abnormalities [1,2]. Along with the development of sepsis, excessive inflammation often leads to distant organ failure, including septic shock, acute respiratory distress and multiple organ dysfunction syndrome [3]. Globally, the annual incidence of sepsis is ∼18 million, which continues to increase at an alarming rate of 8% [4]. Mortality resulting from sepsis is ∼30%, and increases with patient age [5,6]. While the majority of patients die at the late stage of sepsis owing to obvious immunosuppression characterized by hypoinflammation and impaired immune responses [7,8], there have been reports of patient deaths at the early stages due to excessive activation of the immune response [9]. The current clinical treatments for sepsis, such as organ function support, antibiotics and oxygen administration, are non-specific [2]. Therefore, improved understanding of the pathophysiological, immunological and molecular mechanisms that regulate the development and progression of sepsis is essential to provide more effective therapies.
Thioredoxin (TRX) 2, also known as mitochondrial thioredoxin, is a TRX family member widely expressed in both prokaryotes and eukaryotes that containsa redox-active disulfide/dithiol group within a conserved active sequence [[10], [11], [12]]. TRX-2 plays crucial roles in protection against oxidant-induced apoptosis and mitochondrial membrane potential regulation. Downregulation of TRX-2 is reported to result in increased reactive oxygen species (ROS) generation and cell death [13]. Forred et al. showed that oxidized TRX-2 and peroxiredoxin-3 (PRX-3) accumulate during hyperoxic injury of human lung epithelial cells. Inhibition of redox cycling via thioredoxin reductase-2 (TRXR-2) promoted hyperoxic cell death. Moreover, shRNA knockdown of TRX-2 enhanced phosphorylation of apoptosis signal-regulating kinase-1 (ASK1) [14]. Another report focused on the role of TRX-2 inischemic preconditioning (IPC)-mediated neuroprotection against oxidative stress. The group demonstrated that by maintenance of TRX-2 expression, IPC exerts a neuroprotective effect against ischemic injury, suggesting that maintenance or enhancement of TRX-2 expression by IPC may serve as a potential therapeutic intervention for cerebral ischemia [15]. In view of the antioxidative role of TRX-2 and significant association of oxidative stress with inflammatory responses in sepsis [16,17], we hypothesized that TRX-2 plays a protective role against sepsis-induced lethality.
Data from the present study revealed decreased TRX-2 expression in macrophages stimulated with LPS. Overexpression of TRX-2 significantly inhibited mortality in mouse sepsis models, which was associated with reduction of inflammatory cytokine production and attenuation of organ injury. TRX-2 inhibited LPS-induced inflammatory responses through suppressing activation of NF-κB and MAPK signaling pathways. Taken together, our findings support a role of TRX-2 as a critical regulator of sepsis that determines influences survival by protecting the host from excessive inflammatory damage.
Section snippets
Reagents and mice
Lipopolysaccharide (LPS) was purchased from Sigma–Aldrich (St. Louis, MO, USA). Antibodies specific for TRX-2, phospho-p65, p65, phospho-ERK1/2 (p- ERK1/2), ERK1/2, phospho-p38 (p-p38), p38, phospho-JNK, JNK and GAPDH were obtained from Cell Signaling Technology (Beverly, MA, USA). ELISA kits for TNF-α, IL-6 and CCL2 were acquired from R&D Systems (Minneapolis, MN, USA). All male C57BL/6 mice (6–8 weeks of age) used in the experiments were purchased from Shanghai SLAC Laboratory Animal Co. Ltd
Expression of TRX-2 in LPS-induced murine peritoneal macrophages and RAW 264.7 cells
To explore the role of TRX-2 in macrophages, we initially examined TRX-2 mRNA expression in response to LPS stimulation. The TRX-2 mRNA level in pM stimulated with LPS was gradually reduced with increasing time-points (Fig. 1A). We further determined the response of TRX-2 to LPS stimulation in the mouse macrophage-like cell line, RAW264.7. Consistently, TRX-2 mRNA expression decreased significantly after LPS stimulation for different time-points (Fig. 1B). In addition, TRX-2 protein levels were
Discussion
Sepsis is a global social burden and poses a significant challenge to researchers due to its high occurrence rate and non-specific treatment options [25,26]. The mortality rate is high, since the mechanisms associated with the development and progression of sepsis remain unclear. In the present study, we explored the biological role of TRX-2 in sepsis. Our data provide experimental evidence that TRX-2 attenuates IL-6 and TNF-α production induced by LPS in macrophages in vitro. TRX-2 inhibited
Declaration of competing interest
The authors declare that they have no conflict of interest.
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