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.
The study, published April 11, 2019 by Cell Metabolism, was led by senior author Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology and Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases at UC San Diego School of Medicine, and first author Elsa Sanchez-Lopez, PhD, a senior postdoctoral researcher in Karin's lab.
Study - Nature - Karin - Team - Mitochondria
In a 2018 study published in Nature, Karin's 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," Karin said. "But at the time we didn't have a good way to induce mitophagy."
Sanchez-Lopez - Macrophages - Uptake - Choline - Metabolism
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 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," Karin said.
Ability - NLRP3 - Inflammasome - Living - System
To test their new ability to control NLRP3 inflammasome in a living system, the...
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