What about post infection reprogramming of macrophages?

Not dead yet!

Well-Known Member
I found an interesting article today that seems related to ME/CFS. It says that if you have a Salmonella infection, then your macrophages can be reprogrammed to produce less pyruvate in the mitochondria. And that iron supplements can reverse that. I'm not sure I can use that advice since I constipate with iron supplements but maybe there's an IV solution I should look for.

In my subjective memory, I did get a food poisoning incident before I started having severe issues with exhaustion. Before that event, I would occasionally have to take a rest day every few weeks, but I considered that normal. What was never normal about me was that I would occasionally get overstimulated even as a child and need to immediately stop doing what I was doing and lie down. That didn't happen often though.

After the food poisoning, I think Celiac activated and possibly some changes to my immune system occured. In that time period someone told me to take iron supplements too. But I couldn't, it made me constipated, even the SlowFe.

So anyway, this is the article, if it helps: http://microbialcell.com/researcharticles/2019a-telser-microbial-cell/

There doesn't seem to be a paywall. But here's an excerpt. The new site looks great, but we seem to have lost the "article" function. So I'll use quote.

DISCUSSION

Based on the evidence that both the activation of the mTOR pathway and perturbations of iron homeostasis have subtle effects on different metabolic pathways in cells [1][4][36] and because both affect the course of infectious diseases [25][32], we herein studied their impact on metabolic profiles in Salmonella infected macrophages and investigated for a putative functional interaction in that setting. We found that upon Salmonella infection metabolic reprogramming characterized by a well described Warburg effect occurs as reflected by induction of aerobic glycolysis [24]. Accordingly, in Salmonella infected cells increased lactate and reduced pyruvate levels were found while glutamine and alpha-ketoglutarate concentrations were reduced in cellular supernatants. Glutamine, which is present in culture medium can be consumed by cells and converted to glutamate by glutaminase, which then enter in the TCA cycle upon conversion to alpha-ketoglutarate. This could suggest that upon stimulation of anaerobic glycolysis in the course of infection the cells switch to the use of glutamine to feed TCA cycle.



In addition, iron loading of infected RAW264.7 murine macrophages resulted in induction of TCA activity and reduction of anaerobic glycolysis as evidenced by increased pyruvate and reduced lactate levels. Most interestingly, we provide additional novel information that iron perturbations do not only affect enzymatic activities but also impact on the mRNA expression of the TCA enzymes aconitase (Aco), isocitrate dehydrogenase (IDH) and succinate dehydrogenase (SDH), however, these effects have been slightly different between resting and infected macrophages (Fig. 1 and 2). An effect of iron on TCA activity has so far been mainly attributed to translational regulation of mitochondrial aconitase expression via IRE/IRP interaction [37] but also referred to a direct effect of the metal on enzymatic activities of TCA enzymes as shown in different cellular systems [9][11]. This may be linked to alterations in the concentrations of enzymatic substrates or a direct impact on the catalytic centers of these enzymes which often contain iron-sulfur clusters [38]. Moreover, the mechanisms by which iron alters the expression of TCA enzymes deserved further analysis of the underlying mechanism but may include epigenetic control by TCA derived carbohydrates and posttranslational regulation of enzyme activities. Of note, we also found that Salmonella infection per se resulted in alterations of mRNA expression of some of the TCA enzymes investigated indicating that either innate immune effector molecules or the pathogen by itself impact on their expression and thus metabolic alterations [19][39][40]. However, some of these effects could be blocked by the addition of rapamycin indicating that mTOR mediated mechanisms play a central role in regulation of TCA enzymes in the course of infection which may be, however, also affected by the pathogen [41][42].



Nonetheless, iron loading of macrophages resulted in metabolic programming of macrophages and altered expression of metabolic enzymes. To better understand these alterations, we looked at the activity of the mTOR signaling pathway since prior studies revealed that mTOR may drive the shift towards aerobic glycolysis in acute inflammation [25]. Our results are in line with activation of mTOR pathway in the course of Salmonella infection of macrophages as reflected by increased phosphorylation of the downstream target of mTOR, 4E-BP1. In addition, inhibition of mTOR by rapamycin resulted in higher bacterial numbers further supporting the role of mTOR in the control of bacterial infection [26][43]. However, iron accumulation caused metabolic re-programming but had no direct effect on mTOR activity as evidenced by unaltered phosphorylation of 4E-BP1 (Fig. 4). This would imply that iron availability controls another target of mTOR activity which translates into the Warburg effect. In this context, hypoxia inducible factor 1 (HIF1) has attracted interest as HIF1 activation is centrally involved in transmitting the metabolic effects mediated by the mTOR pathway [24]. On the other hand, the stability of HIF-1 is controlled by iron via its regulatory effect on prolyl-hydroxylases in a way that high iron availability promotes prolyl-hydroxylase activity which then degrades HIF1 [44][45]. Given the dominant regulatory role of iron for metabolic regulation of infected macrophages it is not surprising that mTOR affects iron in order to limit iron availability and to reduce metabolic reprograming effects. Previous data demonstrated that the tandem zinc finger protein TTP, which is a downstream target of mTOR gets activated in response to rapamycin under low iron conditions or in the presence of an iron chelator. Thereby, TTP negatively regulates the expression of TfR1, leading to reduced iron import [28]. Accordingly, we found a reduction of TfR1 protein expression and reduced ferritin levels upon iron challenge in Salmonella infected macrophages treated with rapamycin. This would indicate that mTOR aims at increasing cellular iron acquisition and efficient storage of the metal within ferritin in order to reduce the proportion of metabolically active iron within the cell. Of interest, we also found that upon inhibition of the mTOR pathway by rapamycin in Salmonella infected macrophage bacterial numbers significantly increased and metabolic profiles partially changed, however, surprisingly with only little effect on pyruvate and lactate levels. Of note, iron administration to rapamycin treated macrophages further increased bacterial numbers which could on the one hand be due to the fact that mTOR inhibition increased intracellular iron availably for bacteria which serves as a microbial nutrient and that iron inducible metabolic effects result in a pathogen friendly intracellular environment (Fig. 7). Most strikingly, under these circumstances iron induces metabolic reprogramming. Of note, the combined treatment of Salmonella infected macrophages with rapamycin and iron resulted in the accumulation of several TCA and branched chain amino acid metabolites. Specifically, the increased concentrations of glutamine and alpha-ketoglutarate as well as of malate in the supernatant suggest problems of feeding the TCA cycle under these combined conditions. The reasons for this remain elusive but may include counter-regulatory mechanisms on enzymatic pathways as well as alterations of mitochondrial function and oxidative stress responses and in addition, effects of the pathogen on metabolic profiles of host cells have also to be considered [46].



One limitation of our study is attributed to the fact that we only investigated RAW 264.7 cells, a well-established model to study macrophage biology and intracellular infection. However, we did not validate those findings in murine primary cells or macrophages isolated from infected mice thus far, an issue with must be followed up in future.



In summary, our data indicate that both, the mTOR pathway and iron perturbations have central regulatory effects on metabolic pathways in the course of infection of macrophages with the intracellular bacterium Salmonella enterica serovar Typhimurium (S. Tm) (Fig. 8). While mTOR activation induces the Warburg effect and anaerobic glycolysis, iron can cause metabolic re-programming toward TCA activation and aerobic glycolysis which may be partly referred to interference with mTOR inducible metabolic processes. Of note, mTOR function and iron homeostasis are functionally connected with mTOR impacting on cellular iron availability. In addition, iron loading of macrophages affects additional metabolic pathways even when mTOR activity is blocked. Thus, iron may not only act as a primary growth factor for bacteria but also create a microbe friendly metabolic environment within cells. Further studies should investigate the importance of this finding in animal models of infection and further characterize the molecular and metabolic interactions between iron and mTOR and their importance for the control of infectious disease by the host [16][17][40].
 

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