Interferon Gamma Induces Reversible Metabolic Reprogramming of M1 Macrophages, 2018, Wang et al.

[jnmaciuch]

Interferon Gamma Induces Reversible Metabolic Reprogramming of M1 Macrophages to Sustain Cell Viability and Pro-Inflammatory Activity

Feilong Wang ∙ Song Zhang ∙ Ryounghoon Jeon ∙ Ivan Vuckovic ∙ Xintong Jiang∙ Amir Lerman∙ Clifford D. Folmes ∙ Petras D. Dzeja ∙ Joerg Herrmann

Highlights

• Interferon gamma (IFNγ) induces a rapid switch to aerobic glycolysis in M1 macrophages sustaining two signaling pathways.
• Repurposing of the mitochondria, including reactive oxygen species production, allows for HIF-1α and IL-1β production.
• ATP production by glycolysis allows for JAK activity, STAT-1 phosphorylation, iNOS and thereby nitric oxide production.

Inflammatory cells like macrophages, upon activation, switch their energy metabolism from the mitochondria to the processing of glucose. This switch feeds into the inflammatory action of macrophages and links it to the glucose concentration in the cell environment.

Accordingly, under conditions of high glucose concentrations, as seen in patients with diabetes, a higher level of inflammatory activity might be seen.

Performing these studies with the macrophage activator interferon gamma that plays a role in the development of narrowing of arteries (atherosclerosis) furthers the potential link of these findings to the more diffuse and aggressive nature of atherosclerosis in diabetic patients.

Abstract
Classical activation of M1 macrophages with lipopolysaccharide (LPS) is associated with a metabolic switch from oxidative phosphorylation to glycolysis.

However, the generalizability of such metabolic remodeling to other modes of M1 macrophage stimulation, e.g. type II interferons (IFNs) such as IFNγ, has remained unknown as has the functional significance of aerobic glycolysis during macrophage activation.

Here we demonstrate that IFNγ induces a rapid activation of aerobic glycolysis followed by a reduction in oxidative phosphorylation in M1 macrophages.

Elevated glycolytic flux sustains cell viability and inflammatory activity, while limiting reliance on mitochondrial oxidative metabolism.

Adenosine triphosphate (ATP) distributed by aerobic glycolysis is critical for sustaining IFN-γ triggered JAK (Janus tyrosine kinase)-STAT-1 (Signal Transducer and Activator of Transcription 1) signaling with phosphorylation of the transcription factor STAT-1 as its signature trait.

Inhibition of aerobic glycolysis not only blocks the M1 phenotype and pro-inflammatory cytokine/chemokine production in murine macrophages and also human monocytes/macrophages.

These findings extend on the potential functional role of immuno-metabolism from LPS- to IFNγ-linked diseases such as atherosclerosis and autoimmune disease.

[Paragraph breaks added for readability]
[Obligatory mention that "M1 macrophage" is a very oversimplified term, but I don't think it detracts from the findings]

Link | PDF

 

[jnmaciuch]

Additional background from the introduction:

[...] a “switch” from oxidative phosphorylation (OXPHOS) to aerobic glycolysis is not only a hallmark of T cell activation but required for T cell effector functions such as IFN-γ production (Chang et al., 2013; Peng et al., 2016). Of interest, while type II IFNs are known to lead to classical M1 macrophages, it is less well known if they induce a metabolic switch similar to LPS. Importantly, type I IFNs such as IFN-α have been shown induce alternative changes in the cellular metabolism of plasmacytoid dendritic cells consisting of increased fatty acid oxidation and OXPHOS (Wu et al., 2016).

 

[jnmaciuch]

Explain like I'm brain-foggy:

Background:
Glycolysis is the first step in cellular metabolism. It can produce some ATP on its own, but most cells use the output of glycolysis for oxidative phosphorylation, which produces more ATP per initial glucose molecule.

However, it has been observed that immune cells often upregulate glycolysis, likely because it can be used to generate ATP much faster (as long as glucose is available).

The goal of this paper was to figure out if (and how) interferon gamma stimulation and metabolism changes were directly related in mediating macrophage signaling.

Findings:
HIF-1 dependent signaling molecules (i.e. IL-1B) as well as nitrous oxide (NO, downstream of JAK/STAT signaling) were dependent on a switch to glycolysis after interferon gamma stimulation.

This signaling was not observed if either metabolic reprogramming was blocked or interferon gamma was not administered, indicating that both are necessary.

TNF-a and IL-6 production was independent of metabolic reprogramming.

Conclusion:
Some, but not all, of the signaling pathways induced in macrophages by interferon gamma stimulation are dependent on changes in macrophage metabolism.

[My note: It is possible that itaconate is one factor that drives that metabolic reprogramming in response to interferon gamma]

 

[forestglip]

HIF-1 dependent signaling molecules (i.e. IL-1B) as well as nitrous oxide (NO, downstream of JAK/STAT signaling) were dependent on a switch to glycolysis after interferon gamma stimulation.

Thank you for the simplified summaries. Could you say what HIF-1 and JAK/STAT are?

 

[jnmaciuch]

Thank you for the simplified summaries. Could you say what HIF-1 and JAK/STAT are?

No problem! HiF-1 is hypoxia inducible factor (a nobel prize winning discovery where one of the winners has quite the history of fraud, if you're interested in a rabbit hole).

It's a transcription factor that normally activates under conditions of oxygen deprivation, though there are some other situations that lead to HIF-1 signaling (such as in this paper).

JAK/STAT is a signaling pathway where recognition of an appropriate signal at the cell surface (e.g. interferon gamma) leads to JAK "activating" STAT, which is another transcription factor.

In both cases, you have initial signal --> transcription factor --> transcription of genes that enable further macrophage signaling (i.e. IL-1B or iNOS)

 

[forestglip]

No problem! HiF-1 is hypoxia inducible factor (a nobel prize winning discovery where one of the winners has quite the history of fraud, if you're interested in a rabbit hole).

It's a transcription factor that normally activates under conditions of oxygen deprivation, though there are some other situations that lead to HIF-1 signaling (such as in this paper).

JAK/STAT is a signaling pathway where recognition of an appropriate signal at the cell surface (e.g. interferon gamma) leads to JAK "activating" STAT, which is another transcription factor.

In both cases, you have initial signaling pathway --> transcription factor --> transcription of genes that enable further macrophage signaling (i.e. IL-1B or iNOS)

Thank you!