Microvesicle-transferred mitochondria trigger cGAS-STING and reprogram metabolism of macrophages in sepsis, 2025, Ji et al

[hotblack]

Microvesicle-transferred mitochondria trigger cGAS-STING and reprogram metabolism of macrophages in sepsis

Ji T, Zhao T, Long S, Wei C, Cheng D, Chen J, Kuang L

Abstract
The inflammatory cytokine storm is a hallmark of sepsis and is highly correlated with organ injury. Therefore, inhibiting inflammatory cytokine production is a straightforward strategy for effectively treating this disease. In this study, we found that microvesicles from lipopolysaccharide (LPS)-primed macrophages could transfer mitochondria to other macrophages and alter their biological functions.

Microvesicles were isolated from LPS-primed macrophages and characterized by transmission electron microscopy. The function of microvesicle-transferred mitochondria in macrophages was evaluated by assessing the expression levels of inflammatory cytokines using immunofluorescent and quantitative real-time polymerase chain reaction (RT-qPCR) assays, and metabonomics using in vitro and in vivo models. Microvesicles derived from LPS-primed macrophages were able to transfer mitochondria to other macrophages. Functionally, these microvesicles induced classical activated macrophage (M1) polarization, reduced phagocytic capacity, altered mitochondrial homeostasis and metabolism in macrophages, and ultimately caused organ injury in vivo.

Mechanistically, we demonstrated that metformin could inhibit the microvesicle-transferred mitochondrial reactive oxygen species (mtROS) and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-Interferon Beta (IFN-β) signaling activity, subsequently reducing inflammatory cytokine production. Our findings suggest that mtROS production is a critical cellular response in the inflammatory cytokine storm of sepsis, and the cGAS-STING-IFN-β signaling pathway may be a novel therapeutic target for sepsis treatment.

Link (Microbiol Spectr)
https://doi.org/10.1128/spectrum.00781-25

 

[jnmaciuch]

This is an interesting paper. Broadly, it seems that the findings can be broken down into a few main points:

1) stimulated macrophages release mitochondria
2) other macrophages can take up these mitochondria and subsequently begin to release certain pro-inflammatory cytokines, independent of any additional stimulation
3) injecting extracellular vesicles from stimulated mitochondria into the circulation of rats induces organ damage consistent with sepsis

Looking at the methods, it seems like they took extra steps to try to make sure that they were not capturing residual LPS (fragment of bacterial cell walls that they used to induce a response in cultured macrophages that MVs were collected from). However, there is still the possibility that something other than mitochondria is making it into these MVs and causing phenotypic changes in macrophages. In order to confirm it was the [edit: mitochondria] themselves, they would have needed to rupture the MVs, purify mitochondria as much as possible, and then put the mitochondria back in sterile MVs. Much easier said than done, though.

For main point #3, we don't really know the cascade of steps between injection of MVs into the tail vein of mice and subsequent organ damage. It doesn't look like they assessed whether the mitochondria in the MVs were actually making it to other tissues. If mitochondrial transfer is happening and changing how immune cells behave, it may only be those near the site of actual injection that are actually taking them up, and the consequences in other tissues are the result of a chain reaction from cytokines released into the circulation.

 

[jnmaciuch]

These results also seem to suggest that something about LPS stimulation changes macrophage mitochondria in a way that causes the release of more cytokines than just interferon when transferred to a naive macrophage. Blocking cGAS STING and interferon beta seems to block sepsis largely because interferon is a sensitizer and would be amplifying things like IL-6 or IL-1 production. But we know that interferon itself doesn't cause sepsis. Extreme cases of interferon production result in tissue damage largely through calcification, not through classical immune-mediated cell damage.

So the interesting question would be: if macrophages received mitochondria from other cells stimulated solely by cGAS-STING/interferon, would they start producing only interferon, or would they also produce a bunch of other cytokines associated with sepsis? If the latter, we would be able to exclude mitochondrial transfer to macrophages as a relevant phenomenon in ME/CFS.