
n mice with Muckle-Well syndrome, an inflammatory condition caused by mutations in NLRP3 genes, treatment with a choline kinase inhibitor reduces inflammation, as evidenced by the smaller spleens on the right, compared to mock-treated mice (three larger spleens on left).
Treatment with a choline kinase inhibitor prompts immune cells to clear away damaged mitochondria, thus reducing NLRP3 inflammasome activation and preventing inflammation
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 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.
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.”
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.
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)-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.
Learn more: In Mice, Eliminating Damaged Mitochondria Alleviates Chronic Inflammatory Disease
The Latest on: Chronic inflammatory disease
via Google News
The Latest on: Chronic inflammatory disease
- ‘Huge leap’ in understanding of eczema could lead to revolutionary new treatments for inflammatory conditionson January 21, 2021 at 11:05 am
The findings could open avenues for treatments for other illnesses, such as rheumatoid arthritis and inflammatory bowel disease ...
- Herbal Medicine Diuretic and Anti-Inflammatory Pill Can Achieve Significant Curative Effect in Treating Chronic Epididymitis Compared with Antibioticson January 21, 2021 at 9:31 am
After more than 30 years of clinical experience, Dr. Li Xiaoping in Wuhan TCM Clinic invented Diuretic and Anti-inflammatory Pill, which relieved countless patients with chronic epididymitis from pain ...
- Neurent Medical Closes $25 Million Series B Funding to Advance Innovative Chronic Rhinitis Treatmenton January 20, 2021 at 9:58 pm
Neurent Medical, a company pioneering innovative treatments for chronic inflammatory sino-nasal diseases, today announced it has closed a $25 million Series B financing. The round was led by new ...
- Chronic Inflammation and Breast Cancer: Is There a Link?on January 19, 2021 at 2:25 pm
There's been a lot of research on a potential link between chronic inflammation and breast cancer. For example, some studies show that chronic inflammation may lead to a higher risk of breast cancer ...
- This common food may increase risk of dangerous bowel diseaseson January 19, 2021 at 3:02 am
In a recent study at Stony Brook University, researchers found that consumption of fructose may worsen intestinal inflammation common to inflammatory bowel diseases (IBD). The study is published ...
- Owlstone Medical introduces breath biopsy panel for respiratory diseaseson January 19, 2021 at 2:02 am
Owlstone Medical, the leader in Breath Biopsy® for applications in disease detection, today introduced the Respiratory Diseases Research Use Only Panel.
- How Anti-Inflammatory Drugs Market Booming Worldwide? Fortune Business Insightson January 18, 2021 at 4:27 pm
Inflammatory Market Industry “ is expected to reach USD 191.42 billion by 2027 on account of increasing investments on the development of biologics for treating autoimmune inflammatory diseases.
- What it's Like to Live with Psoriatic Arthritis During the Pandemic: 'This Disease Does Not Define You'on January 14, 2021 at 2:05 pm
Prioritizing healthy living throughout a global pandemic has been incredibly difficult for everyone. And many of those with chronic, pre-existing conditions face additional challenges. Once such ...
- 5 Delicious Family Meals to Help Curb Chronic Inflammationon January 13, 2021 at 12:24 pm
A new kid-friendly cookbook serves up yummy, nutritious recipes to help thwart illness and fight the obesity epidemic.
- Tissue stiffness likely drives immune responses in many chronic diseaseson January 12, 2021 at 8:01 am
Stiffness in our tissues causes tension in our cells. Research from the Buck Institute, the University Health Network (University of Toronto), Stanford University, and the University of Alberta shows ...
via Bing News