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Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone by uncoupling mitochondria or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state.
Mitochondrial metabolites and their derivatives have been the focus of recent efforts to develop new anti-inflammatory therapeutics. The widely used therapeutic agents dimethyl fumarate (DMF) and metformin have anti-inflammatory properties and have been shown to target metabolism. The mitochondrial metabolites succinate, itaconate, and fumarate have multiple immunomodulatory effects and present interesting therapeutic possibilities for immune and inflammatory diseases. Mitochondrial DNA and double-stranded RNA have also been shown to be highly inflammatory, acting via specific pattern recognition receptors (PRRs) such as cGAS and TLR9 for mitochondrial DNA, RIG-I, MDA5 for mitochondrial double stranded RNA, and TLR7 for mitochondrial single stranded RNA. These recent discoveries are changing our view of mitochondria suggesting that they are at the heart of multiple inflammatory diseases and provide opportunities for the development of new anti-inflammatory therapeutics.
The dangers of passive smoking have been discussed widely and it has become commonplace for smoking to be banned in public places in many countries. Several studies have examined allergic responses in the children of mothers who smoke, with particularly strong evidence indicating that in children with asthma, there is a link between passive smoking and disease severity. However, the role of passive smoking in atopic sensitization is more controversial. A recent study by Rumold and colleagues from the University of California School of Medicine, USA has demonstrated that exposure of mice to passive smoke can augment primary sensitization to an inhaled innocuous protein. Levels of IgE and IgG1 were raised, and there was an influx of eosinophils into the lungs and increased production of the cytokines IL-5, GM-CSF and IL-2, with a concomitant decrease in the production of IFN-γ. The results suggest that passive smoking can induce allergic sensitization to normally harmless antigens and might explain observations indicating that passive smoking is a risk factor for the development of allergy in children. With parental smoking having a prevalence of 40–60%, the results have important implications for public health. J. Immunol. (2001) 167, 4765–4770 LON
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No abstract is provided for this article.
No abstract is provided for this article.
