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We wondered whether the GSH requirement in the induction of genes in the IFN response pathway in Group 2 was biologically relevant. Therefore, we investigated the effect of LPS on PR8 influenza virus infection in RAW cells in which GSH had been depleted by BSO.

As shown in Figure 8 , when cells were infected with PR8, LPS reduced infection, in terms of intracellular viral protein production; influenza nucleoprotein NP, the most expressed among the viral proteins was significantly decreased in cells pretreated with LPS.

However, the effect of LPS was not observed in GSH-depleted cells. Although, as reported previously, BSO alone increased NP production 21 , the treatment with both LPS and BSO induced a further significant increase.

Figure 8. LPS activation of antiviral innate immunity is dependent on GSH. A Western blot for influenza virus proteins in RAW cells infected with PR8 or uninfected, after LPS treatment, with and without GSH depletion.

β-Actin was used as loading control. B Levels of NP viral protein in RAW cells pretreated with LPS, with and without GSH depletion. GSH, glutathione; LPS, lipopolysaccharide; NP, nucleoprotein. We next asked the question whether the inhibitory effect of GSH on Group 1 genes, as revealed by the upregulation by BSO, might be due to its ROS-scavenging antioxidant action.

To answer this, we first investigated whether the induction of Group 1 genes by LPS was inhibitable by the thiol antioxidant NAC. Second, to investigate whether ROS generation induced by LPS could have a role in the induction of Group 1 genes, we asked whether a ROS-generating agent menadione would reproduce the effect of LPS.

As shown in Figure 9 , NAC did not alter the induction of selected Group 1 genes Srx1, Prdx1, Slc7a On the other hand, all these genes were induced by menadione alone. Figure 9. Effect of NAC and menadione on Group 1 left and Group 2 right genes.

Menadione Men was added at 10 µM for 2 h. Gene expression was measured by qPCR. Data are expressed as fold change vs one of the control samples, and are the mean ± SD of six biological replicates from two independent experiments.

LPS, lipopolysaccharide; NAC, N -acetyl- l -cysteine; qPCR, quantitative polymerase chain reaction. The same experimental framework was used to study the relevance of the ROS scavenging properties of GSH in its permissive role for the induction of Group 2 genes. Opposite to what observed with Group 1 genes, menadione by itself was unable to regulate the expression of any of Group 2 genes measured.

This study supports the view that endogenous GSH plays a pivotal role for the establishment of the innate immune responses to viruses, possibly acting as a signaling molecule with a mechanism different from simple scavenging of ROS.

The fact that the vast majority of transcripts were unaffected by BSO is also an indirect confirmation that, within the concentrations and incubation times used, BSO does not have significant toxic or non-specific effects.

The observation that GSH depletion does not exacerbate the transcription of inflammatory genes, at least in our experimental conditions, might seem at variance with the existing literature starting from pioneering paper by Schreck et al.

However, most of that evidence is based on in vitro or in vivo experiments using exogenously administered thiol antioxidants or pro-oxidants.

What our data do not support is the extrapolation of evidence from those experiments to the conclusion that GSH is an endogenous anti-inflammatory molecule through its ROS-scavenging activity.

In fact, previous reports noted that exogenous GSH or its precursor NAC inhibits the production and expression of TNF, IL-6, and IL-8 by LPS-stimulated macrophages in the absence of any significant change in intracellular GSH The results reported here are also in agreement with our previous studies where we observed that there are more H 2 O 2 -induced genes that require GSH for their upregulation than genes whose induction by H 2 O2 is exacerbated by GSH depletion Interestingly, in that study using human monocytic cells, many of the H 2 O 2 -induced genes for which GSH had a facilitatory role were related to immunity In addition, the only LPS-induced transcripts mapping to innate immunity in their functional annotation were inhibited, rather than upregulated, by GSH depletion Group 2 genes.

Not only innate immunity genes in Group 2 require GSH for their induction but also they were not induced by ROS alone using menadione as a ROS-generating chemical and their LPS induction was not inhibited by NAC, ruling out the possibility that ROS act as signaling molecules in their induction by LPS.

The only exception was il1b whose LPS induction was inhibited by NAC but was also inhibited by GSH depletion, suggesting that GSH is important for IL-1b induction by LPS but possibly not through an antioxidant mechanism because i exogenous NAC and endogenous GSH appear to have an opposite role, and ii an oxidant alone does not induce IL-1b expression.

In line with these findings, it has been shown that molecules altering intracellular thiol content with different mechanisms i. The innate immune response is also important for antiviral defense and activation of TLR4 leads to induction of antiviral proteins including IFNs and IFN-related genes 27 , 28 such as MxA and Oas 29 , Our data, although obtained in a model where infectivity was low, suggest that GSH is important for the activation of an antiviral response.

This happens without affecting inflammatory genes, except for IL-1b whose induction was also facilitated by the presence of GSH. There is evidence for a fine-tuning of TLR signaling 31 , and these data indicate that GSH may be important in directing it toward specific small patterns of genes implicated in host defense rather than toward those responsible for the inflammatory response, as outlined in Figure Figure GSH fine-tuning of TLR4 signaling.

GSH orients the TLR4-mediated changes in gene expression profile toward activation of host defense. GSH, glutathione; LPS, lipopolysaccharide; TLR4, toll-like receptor 4. The behavior of genes in Group 1 is what one would expect.

They include enzymes for GSH synthesis and antioxidant enzymes such as Prdx1, Srxn1, and Hmox. All these genes map to nrf2, a master regulator of redox homeostasis Their regulation by BSO is in accordance with the hypothesis that endogenous GSH acts as an ROS scavenger because menadione induces their expression.

However, NAC did not inhibit their induction by LPS, suggesting that LPS induces nrf2 target gene expression independently of the increase in ROS production.

This agrees with a recent study by Cuadrado et al. showing that LPS can activate nrf2 via the small GTPase RAC1, independently of ROS In this picture, endogenous GSH might be important through other mechanisms than just scavenging ROS.

In fact, nrf2 activation is dependent on oxidation of its redox sensor, keap1. Several studies have indicated that activation of nrf2 by administration of electrophilic compounds has an anti-inflammatory effect and decreases LPS-induced transcription of other NF-kB target genes, including TNF, IL-1b, and IL-6, in RAW cells 35 , However, as mentioned earlier, in our experimental conditions in which nrf2 was likely activated by GSH depletion, as suggested by the increased expression of nrf2 target genes, we have not observed an effect on any inflammatory cytokine other than IL-1b.

Once again, the difference might be that we did not use exogenous electrophiles to induce nrf2. This highlights one point that is often overlooked. GSH is not just an antioxidant that participates in ROS elimination either via its direct ROS scavenging activity or as a substrate for GSH peroxidases but, like any other thiol including NAC, is also a reducing agent, as well as GSSG is a thiol oxidizing agent.

Therefore, these two molecular species, GSH and GSSG, can regulate biological pathways in a redox-dependent manner, independently of ROS scavenging. In fact, protein glutathionylation is a major mechanism of redox regulation of immunity 10 , 37 , affecting the function of key proteins including NF-kB 38 , STAT3 39 , PKA 40 , TRAF3, and TRAF6 41 , as well as participating in the release of danger signals 42 , However, in this experimental model, the induction of host defense genes in Group 2 at least those shown in Figure 7 , il1b, Mx2, and Irf9 is inhibited by BSO, evidencing the need for GSH, but is not amplified by NAC, suggesting that scavenging LPS-induced ROS is not the main mechanism of action of endogenous GSH.

The finding that several genes that are important for the antiviral response, mostly part of IFN signaling pathways, including the antiviral proteins Oas and Mx2, require GSH for optimal induction by LPS adds knowledge to previous findings, indicating that GSH can inhibit viral infection 44 , 45 and that viral infection causes release of glutathionylated thioredoxin and Prdx There is a large body of evidence showing the importance of GSH in immunity, including antiviral immunity 47 , but so far this was ascribed to its action as ROS scavenger to inhibit oxidative stress.

The present study indicates that GSH has other important signaling roles independently of protection from oxidative stress, and its action may not be vicariated by another thiol antioxidant.

However, to understand the validity of our conclusions to other models, one needs to bear in mind the limitations of this study that is investigating mRNAs in a cell line. Future studies will need to measure the proteins of interest for instance, IL-1b to see whether the changes observed at the level of transcripts are reflected in changes in protein levels.

To generalize the relevance of this mechanism, the observation will need to be confirmed in primary cells, including human cells, and possibly in vivo.

MD, PC, MM, IC, LC, FP, and KA performed experiments. AH, PG, KA, LC, MM, FP, and AP designed and supervised experiments. MD, PG, MM, FP, and PC wrote the paper.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

This work was supported by a fellowship program from Istituto Pasteur Italia——Fondazione Cenci Bolognetti to PC , PRIN CUP grant number B to AP , and RM Phillips Trust to PG.

File S1. Transcripts in bold are those also significantly affected by BSO alone BSO vs control, with a cutoff of FC 1. The log 2 -transformed gProcessed signals of the three biological replicates are shown.

The FC between the two groups indicated is expressed as log 2 ratio. File S2. NF-kB target genes upregulated by LPS. Transcripts in bold are those in Group 2 significantly affected by BSO with a cutoff of 1.

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