Chronic Inflammatory Diseases

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 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 at University of California San Diego School of Medicine discovered a unique approach that might help treat some chronic inflammatory diseases: force cells to eliminate damaged mitochondria before they activate the NLRP3 inflammasome.
After that, we wondered if they could reduce harmful excess inflammation by intentionally inducing mitophagy; which would eliminate damaged mitochondria and should in turn pre-emptively inhibit NLRP3 inflammasome activation,” Karin said. “But at the time we didn’t have a good way to induce mitophagy.”

Inhibitor of the enzyme choline kinase

More recently, Sanchez-Lopez was studying how macrophages regulate their uptake of choline; a nutrient critical for metabolism, when she discovered something that can initiate mitophagy; an inhibitor of the enzyme choline kinase (ChoK). With ChoK inhibited, choline is no longer 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; finally able to inhibit NLRP3 inflammasome activation. To test their new ability to control NLRP3 inflammasome in a living system, the researchers turned. They discovered that treatment with ChoK inhibitors prevented acute inflammation caused by uric acid (accumulation of which triggers gout flares) and a bacterial toxin.

The ChoK inhibitor treatment

By several measures, ChoK inhibitor treatment also reversed chronic inflammation 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)-1? and IL-18. According to Karin, there are existing drugs that can block IL-1?; but not IL-18. ChoK inhibitors; his team found; can reduce both cytokines. “There are several diseases, including lupus and osteoarthritis, whose treatment will likely require dual inhibition of both IL-1? and IL-18,” Karin said.