Inflammation is a balanced physiological response – the body must eradicate invasive organisms and foreign irritants, but excessive inflammation can damage healthy cells, contribute to aging and chronic diseases. To help keep tabs on inflammation, immune cells use a molecular machine called the NLRP3 inflammation. NLRP3 is inactive in a healthy cell, but is transfused on "stress" or exposure to bacterial toxins damaged in the cell mitochondria (energy generating organs).
However, when the inflammation of NLRP3 becomes stuck in the “forward” condition, it can contribute to some chronic inflammatory conditions, including gout, osteoarthritis, fatty liver disease and Alzheimer's and Parkinson's diseases. In a new study of the mouse, researchers at the University of California San Diego School of Medicine found a unique approach that could help treat chronic inflammatory diseases: applying cells to eliminate damaged mitochondria before acting They become the inflammation of NLRP3.
The study, published April 11, 2019 by Cell metabolism, led by senior author Michael Karin, PhD, Professor of Pharmacology and Pathology and Chairman Ben and Wanda Hildyard for Mitochondrial and Metabolic Diseases at UC San Diego Medical School, and first author Elsa Sanchez-Lopez, PhD, senior postdoctoral researcher Karin lab.
In a 2018 study published in Nature, Karin's team showed that damaged mitochondria acted the NLRP3 inflammation. The researchers also found that the inflammasome NLRP3 is deactivated when the process of mitochondria is removed with the cell's internal waste recycling process, known as mitophagy.
"After that, we thought we could reduce the harmful excess inflammation by mitigating the deliberate mitigation, which would eliminate damaged mitochondria and should in turn activate inflammasome NLRP3, "said Karin. "But at the time we did not have a good way of easing a mound."
Recently, Sanchez-Lopez was studying how macrophages control their adoption of choline, a nutrient that is vital for metabolism, when she discovered something that can initiate mitophagy: inhibitor of the enzyme kinase colon (ChoK). To prevent ChoK, the choline is no longer incorporated in mitacondrost films. As a result, the cells appear to have damaged the mitochondria, and cleaned them with mitigation.
"More importantly, by getting rid of damaged mitochondria with ChoK inhibitors, we were able to eliminate the inflammasome activation of NLRP3," said Karin.
To test their new ability to control inflammasome NLRP3 in a living system, the researchers turned to mice. They found that treatment with ChoK inhibitors prevented severe inflammation caused by uric acid (which stimulates gout bug accumulation) and bacterial toxin.
Through various measures, the treatment of ChoK inhibitors reversed chronic inflammation associated with a genetic disease called Muckle-Well Syndrome, resulting in mutations in NLRP3 genes. One such measure is the size of the spleen – the greater the spleen, the main inflammation. The Muckle-Well mice blinds are twice as large on average as normal mice, but their spleen amounts are normalized after ChoK inhibitors treatment.
NLRP3 inflammasome promotes inflammation because it stimulates two pro-inflammatory molecules called cytokines: interleukin (IL) -1? and IL-18. According to Karin, there are drugs that can block block IL-1, but not IL-18. ChoK inhibitors, his team, can reduce the two cytokines.
"There are some diseases, including lupus and osteoarthritis, which are likely to require two prevention of IL-1 and IL-18 on their treatment," Karin said.
The co-authors of this study are Zhenyu Zhong, Alexandra Stubelius, Laela M. Booshehri, Laura Antonucci, Ru Liu-Bryan, Robert Terkeltaub, Anne N. Murphy, Hal M. Hoffman, Monica Guma, UC San Diego; Shannon R. Sweeney, Alessia Lodi and Stefano Tiziani, University of Texas at Austin; and Juan Carlos Lacal, Universitario Fuenlabrada Hospital, Madrid, Spain.
This research was partly funded by the National Institutes of Health (grants R01AI43477 and R37AI043477, P42ES010337, P50AR060772, 1I01BX002234, R01DK113592, R01AR073324 and R03AR068094), Rotating Tires for Alzheimer's Research (CART), Leukemia & Lymphoma Association (award 7005- 14) VA Research Service Merit Awards (I01BX001660), CymaBay Terapeutics, ISCIII / MICINN (Sara Borrell fellowship), Research Institute Irvington Fellowship, Cancer Directors Prevention Research Fund, American Society for the Study of Disease Ae Pinnacle Research Research Fellowship Award International Cancer (iCARE) and AIRC co-founded by the European Union.
Exposure: The University of California San Diego is engaged in patent applications covering CTL1 use and / or kinase kinase chemical genometers to list NLRP3 related diseases to epilepsy, Michael Karin and Elsa Sanchez-Lopez as inventors.
Full study: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30139-1
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