One mystery of Long COVID - why immune cells get stuck in a harmful, inflammatory mode.
A new study shows the switch is metabolic - and a single checkpoint can decide whether Th17 cells protect or drive disease.🧵
A new study shows the switch is metabolic - and a single checkpoint can decide whether Th17 cells protect or drive disease.🧵
https://twitter.com/atranscendedman/status/1970931377198825678
In both children and adults with Long COVID, we see immune cells stuck in a harmful mode.
Among them - Th17 cells, which can either protect us or drive chronic inflammation.
A new study in Science Signaling, 2025 uncovers why these cells flip - and what keeps them locked in the pathogenic state.
Among them - Th17 cells, which can either protect us or drive chronic inflammation.
A new study in Science Signaling, 2025 uncovers why these cells flip - and what keeps them locked in the pathogenic state.
Th17 cells have two faces -
non-pathogenic (protective, balanced),
pathogenic (autoimmune, chronic inflammation).
The critical switch? Cellular metabolism.
non-pathogenic (protective, balanced),
pathogenic (autoimmune, chronic inflammation).
The critical switch? Cellular metabolism.
When Th17 cells rely on aerobic glycolysis, they become pathogenic.
When they shift to oxidative phosphorylation (OXPHOS) in mitochondria, they stay non-pathogenic.
When they shift to oxidative phosphorylation (OXPHOS) in mitochondria, they stay non-pathogenic.
The key checkpoint is the A2A receptor - AMPK pathway.
AMPK acts as an energy sensor. When activated, it reprograms Th17 cells away from glycolysis and toward OXPHOS.
AMPK acts as an energy sensor. When activated, it reprograms Th17 cells away from glycolysis and toward OXPHOS.
This is not just metabolic. It’s also epigenetic.
AMPK suppresses the co-activator PCAF, reducing histone acetylation on glycolysis genes while opening genes for OXPHOS.
AMPK suppresses the co-activator PCAF, reducing histone acetylation on glycolysis genes while opening genes for OXPHOS.
The result.
Pathogenic programs are silenced.
Non-pathogenic programs are stabilized.
Without this pathway, Th17 cells readily triggered autoimmune disease in mice.
Pathogenic programs are silenced.
Non-pathogenic programs are stabilized.
Without this pathway, Th17 cells readily triggered autoimmune disease in mice.
So AMPK is more than an energy regulator.
It is a checkpoint that determines whether Th17 cells become protectors or drivers of autoimmunity.
It is a checkpoint that determines whether Th17 cells become protectors or drivers of autoimmunity.
This mechanism helps explain the immune switch” we see in Long COVID - where cells remain in a pathogenic mode.
It also points to a possible way to reverse it.
It also points to a possible way to reverse it.
Even though human trials are missing, one well-known AMPK activator - metformin - has already shown signals of reducing the risk or severity of Long COVID.
This new work gives that observation a molecular logic. Activating AMPK doesn’t just change energy use - it can reset the immune program at the epigenetic level.
Papadopoulou et al., Science Signaling (2025). Adenosine 2A receptor–dependent activation of AMPK represses TH17 cell pathogenicity through epigenetic and metabolic reprogramming. science.org/doi/10.1126/sc…
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