Mitochondrial Uncoupling in Macrophages as a Strategy to Reduce Inflammation

Researchers here show that forcing mitochondrial uncoupling in macrophages can change their behavior to resolve inflammation. There are a range of therapeutic approaches that might achieve this goal, as mitochondrial uncoupling has been a target for drug discovery for some time, albeit largely for reasons other than the reduction of inflammation. Uncoupling in mitochondria disconnects their activity from the production of ATP to power cellular operations, leading to heat generation instead. This change influences many other cellular processes, largely in beneficial ways; uncoupling occurs during calorie restriction, and intermittently inducing uncoupling is a calorie restriction mimetic strategy, with accompanying benefits to long-term health. To what degree is a reduction in chronic inflammation in later life driving those benefits? That is an interesting question.

Researchers have recently shown how inflammatory reactions can be resolved by changes to the metabolism of macrophages. Danger signals released by damaged cells during inflammation play a role during this process. 'Rewiring' the mitochondria in the macrophages protects them against overloading and can thus improve the way in which parts of damaged cells are eliminated and resolve the inflammatory reaction. Inflammation is a natural and vital response of our immune system to danger signals and tissue damage. Inflammatory processes help the body to eliminate the triggers, for example bacteria, and to initiate repair mechanisms. Terminating this inflammatory reaction quickly and in a coordinated manner is just as important, however, as otherwise there is a risk of developing chronic inflammatory conditions.

Researchers investigated the function of macrophages at the site where inflammation occurs. These cells are capable of ingesting large quantities of cellular waste and digesting and eliminating the molecular components of this waste in their mitochondria, also referred to as the powerhouse of the cell. The scientists were able to demonstrate that the danger signal interleukin 33, which is released from damaged cells, triggers lasting changes to the metabolism of macrophages, so that their waste disposal capacity significantly increases.

The sheer quantity of waste produced during the inflammatory reaction places the mitochondria under severe strain, and they produce increased quantities of damaging oxygen radicals as a result. Interleukin 33 regulates the function of the mitochondria by initiating a process known as uncoupling in these cell components and protecting them from overloading. "This enables the macrophages to 'let off steam' and carry on ingesting waste without interruption despite the heavy strain placed upon them, resolving the inflammation processes as a result. It may be possible to accelerate and support the resolution of inflammatory processes in the long term by influencing the cell metabolism of the macrophages and deliberately uncoupling their mitochondria."


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