abstract of
the original paper
Abstract
A crucial role of cell metabolism in immune cell differentiation and function has been recently established. Growing evidence indicates that metabolic processes impact both, innate and adaptive immunity. Since a down-stream integrator of metabolic alterations, mammalian target of rapamycin (mTOR), is responsible for controlling the balance between pro-inflammatory interleukin (IL)-12 and anti-inflammatory IL-10, we investigated the effect of upstream interference using metabolic modulators on the production of pro- and anti-inflammatory cytokines.
Cytokine release and protein expression in human and murine myeloid cells was assessed after
toll-like receptor (TLR)-activation and glucose-deprivation or co-treatment with 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activators. Additionally, the impact of metabolic interference was analysed in an
in-vivo mouse model. Glucose-deprivation by 2-deoxy-D-glucose (2-DG) increased the production of IL-12p40 and IL-23p19 in monocytes, but dose-dependently inhibited the release of anti-inflammatory IL-10.
Similar effects have been observed using pharmacological AMPK activation. Consistently, an inhibition of the tuberous sclerosis complex-mTOR pathway was observed. In line with our
in vitro observations, glycolysis inhibition with 2-DG showed significantly reduced bacterial burden in a Th2-prone
Listeria monocytogenes mouse infection model. In conclusion, we showed that fasting metabolism modulates the IL-12/IL-10 cytokine balance, establishing novel targets for metabolism-based immune-modulation.
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This section of the paper, on AMPK, is also interesting.
@ChrisArmstrong's presentation at the symposium explained the way gut dysfunction could trigger AMPK activation and thereby trigger a low energy state.
Apart from its crucial role as a master regulator of cellular metabolic homeostasis, the enzyme adenosine AMPK has been shown to exert an important role in regulation of immunity, [8–10]. Importantly, AMPK controls dendritic and T-cell metabolic adaption and plays a key role in effector responses in vivo [11–13]. Furthermore, it has been demonstrated that AMPK regulates IL-10-mediated anti-inflammatory signaling pathways in murine macrophages [14].
Various extrinsic signals that regulate glucose and amino acid metabolism as well as bacterial stimuli converge on signaling factors of the phosphatidylinositide 3-kinase (PI3K) pathway, including Akt, 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK), and mammalian target of rapamycin (mTOR). These kinases lie at the crossroad of a complex nutrient hormonal signaling network coordinating the regulation of cell metabolism and effector mechanisms of the immune response [12, 15–17]. Recently, it has been shown that mTOR signaling is closely intertwined with the AMPK nutrient sensing pathway that is responsible for processing energy status, insulin, growth factors, and environmental cues, transmitting signals to downstream targets to effectuate both, cellular and the metabolic response [18].
Upon activation, AMPK induces, among other signaling cascades, the formation of the tuberous sclerosis complex (TSC) via phosphorylation of TSC2 and regulatory-associated protein of mTOR (Raptor) [19], which in turn inhibits phosphorylation of mTOR and its downstream targets, ribosomal protein S6 kinase (rpS6k) and 4E-binding protein 1(4E-BP1) [12, 20]. It has previously been reported that inhibition of mTOR by rapamycin in human monocytes or murine macrophages stimulated with lipopolysaccharide (LPS) enhances the production of IL-12 and IL-23, whereas IL-10 is blocked [21–23]. In order to further elucidate the impact of upstream regulation of mTOR signaling on its cytokine modulating effect the present study was aimed at investigating whether metabolic interference by mimicking fasting metabolism via AMPK activation could reproduce the effect of mTOR inhibition on cytokine induction in innate immune cells.
The results show that in human and mouse monocytes, glucose-deprivation with 2-deoxy-D-glucose (2-DG) as well as specific AMPK activators bring about effects similar to mTOR inhibition leading to consistent inhibition of IL-10 production. Furthermore, 2-DG was also able to reproduce the effect of rapamycin in a Listeria infection model leading to profound reduction in bacterial burden.
The paper talks about inhibiting mTor to inhibit IL10. Montoya's cytokine paper shows severe patients have higher IL10 ( not statistically significant after correcting for multiple comparisons but strikes the eye on the graph. It's also not one of the 17 with a linear associaton with severity but it has the general pattern and can't have missed inclusion in that group by much). Obviously in severe patients it's not so simple as being stuck in an AMPK activated, low mTOR, low IL10 state.
