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Combatting Chronic Inflammatory Disease: A Fresh Approach

Research Suggests Novel Path to Regulating the Molecular Machine that Triggers Inflammation

Inflammation—a necessary physiological response to foreign agents and invasive organisms—becomes harmful when excessive or prolonged, contributing to gout, osteoarthritis, and other conditions. Immune cells regulate inflammation via the NLRP3 inflammasome that, when triggered by damage to cell mitochondria, promote inflammation through the release of the cytokines IL-1b and IL-18. There are known agents that can block IL-1b, but not IL-18. But findings from a recent study suggest a novel approach to disarming NLRP3 activation: induce cells to eliminate their damaged mitochondria—a process called mitophagy—before the inflammasome is triggered. Building on earlier work that had identified the mitochondria/inflammasome connection, senior author Michael Karin, PhD, professor at UC San Diego School of Medicine, remarked, “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. But at the time we didn’t have a good way to induce mitophagy.”

A solution was suggested by Elsa Sanchez-Lopez, PhD, a senior postdoctoral researcher in Dr. Karin’s lab, who discovered that mitophagy could be initiated through inhibition of the enzyme choline kinase (ChoK), which caused cells to perceive mitochondria as damaged and eliminate them via mitophagy. The discovery was tested in mouse models, in which treatment with ChoK inhibition was found to successfully reverse chronic inflammation caused by uric acid, and from a genetic disease, Muckle-Well Syndrome. The ChoK inhibition treatment was found to block both the IL-1b and IL-18 cytokines, about which Dr. Karin noted, “There are several diseases, including lupus and osteoarthritis, whose treatment will likely require dual inhibition of both IL-1b and IL-18.” The results were published last week in the journal Cell Metabolism.

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The journal abstract may be read here.