The mitochondrial succinate dehydrogenase complex controls the STAT3-IL-10 pathway in inflammatory macrophages

The functions of macrophages are tightly regulated by their metabolic state. However, the role of the mitochondrial electron transport chain (ETC) in macrophage functions remains understudied. Here, we provide evidence that the succinate dehydrogenase (SDH)/complex II (CII) is required for respiration and plays a role in controlling effector responses in macrophages. We find that the absence of the catalytic subunits Sdha and Sdhb in macrophages impairs their ability to effectively stabilize HIF-1 alpha and produce the pro-inflammatory cytokine IL-1 beta in response to LPS stimulation. We also arrive at the novel result that both subunits are essential for the LPS-driven production of IL-10, a potent negative feedback regulator of the macrophage inflammatory response. This phenomenon is explained by the fact that the absence of Sdha and Sdhb leads to the inhibition of Stat3 tyrosine phosphorylation, caused partially by the excessive accumulation of mitochondrial reactive oxygen species (mitoROS) in the knockout cells.

Automated summary

The subunits Sdha and Sdhb of the mitochondrial electron transport chain play important roles in the respiration and effector responses of macrophages. Their absence impairs the stabilization of HIF-1 alpha and the production of the pro-inflammatory cytokine IL-1 beta in response to LPS stimulation, and also inhibits the production of IL-10. This is due to the excessive accumulation of mitochondrial reactive oxygen species (mitoROS) and the inhibition of Stat3 tyrosine phosphorylation caused by the absence of Sdha and Sdhb.