Inflammation is a balanced physiological response -- the body needs it to eliminate invasive organisms and foreign irritants, but excessive inflammation can harm healthy cells, contributing to aging and chronic diseases. To help keep tabs on inflammation, immune cells employ a molecular machine called the NLRP3 inflammasome. NLRP3 is inactive in a healthy cell, but is switched "on" when the cell's mitochondria (energy-generating organelles) are damaged by stress or exposure to bacterial toxins.
However, when the NLRP3 inflammasome gets stuck in the "on" position, it can contribute to a number of chronic inflammatory conditions, including gout, osteoarthritis, fatty liver disease and Alzheimer's and Parkinson's diseases. In a new mouse study, researchers discovered a unique approach that might help treat some chronic inflammatory diseases: force cells to eliminate damaged mitochondria before they activate the NLRP3 inflammasome. The study was published in Cell Metabolism.
In a 2018 study published in Nature, the team had shown that damaged mitochondria activate the NLRP3 inflammasome. The researchers also found that the NLRP3 inflammasome is de-activated when mitochondria are removed by the cell's internal waste recycling process, called mitophagy.
"After that, we wondered if we could reduce harmful excess inflammation by intentionally inducing mitophagy, which would eliminate damaged mitochondria and should in turn pre-emptively inhibit NLRP3 inflammasome activation," the senior author said. "But at the time we didn't have a good way to induce mitophagy."
More recently, the team was studying how macrophages regulate their uptake of choline, a nutrient critical for metabolism, when they discovered something that can initiate mitophagy: an inhibitor of the enzyme choline kinase (ChoK). With ChoK inhibited, choline is no longer incorporated into mitochondrial membranes. As a result, the cells perceive the mitochondria as damaged, and cleared them away by mitophagy.
"Most importantly, by getting rid of damaged mitochondria with ChoK inhibitors, we were finally able to inhibit NLRP3 inflammasome activation," the senior author said.
To test their new ability to control NLRP3 inflammasome in a living system, the researchers turned to mice. They discovered that treatment with ChoK inhibitors prevented acute inflammation caused by uric acid (accumulation of which triggers gout flares) and a bacterial toxin.
By several measures, ChoK inhibitor treatment also reversed chronic inflammation associated with a genetic disease called Muckle-Well Syndrome, which is caused by mutations in NLRP3 genes. One such measure is spleen size -- the larger the spleen, the more inflammation. The spleens of Muckle-Well Syndrome mice are on average twice as large as normal mice, but their spleen sizes normalized after ChoK inhibitor treatment.
NLRP3 inflammasome promotes inflammation because it triggers the release of two very potent pro-inflammatory molecules called cytokines: interleukin (IL)-1beta and IL-18. According to the senior author, there are existing drugs that can block IL-1beta, but not IL-18. ChoK inhibitors, the team found, can reduce both cytokines.
"There are several diseases, including lupus and osteoarthritis, whose treatment will likely require dual inhibition of both IL-1beta and IL-18," the senior author said.
Alleviating chronic inflammatory disease by eliminating damaged mitochondria
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