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Triggering clean-up lessens inflammation
SAN DIEGO—Inflammation is a cellular and molecular response to infection and/or tissue injury. Timely and suitable inflammatory response kills pathogens, clears necrotic tissue and heals injury, but when the response is excessive, various chronic diseases can emerge. At its worst, inflammation and tissue damage fuel each other in a self-reinforcing loop that contributes to numerous pathological conditions (e.g., autoimmune diseases, diabetes, chronic obstructive pulmonary disease, atherosclerosis, aging, etc.). A recent study published in Cell Metabolism, “Choline Uptake and Metabolism Modulate Macrophage IL-1β and IL-18 Production,” explores how we might prompt cells to eliminate damaged tissue before a potentially toxic inflammatory response begins.
Dr. Michael Karin, Distinguished Professor of Pharmacology and Pathology and Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases at UC San Diego (UCSD) School of Medicine, and first author Dr. Elsa Sanchez-Lopez, a senior postdoctoral researcher in Karin’s lab, had previously reported findings that damaged mitochondria (the main source of cellular energy) activate the molecular NLRP3 inflammasome, and that it is de-activated when the cell’s internal sweepers delete damaged mitochondria, a process called mitophagy. When “on,” NLRP3 produces two very potent pro-inflammatory molecules called cytokines: interleukin (IL)-1 β and IL-18.
“After that, we wondered if we could reduce harmful excess inflammation by intentionally inducing mitophagy, which would eliminate damaged mitochondria and should in turn preemptively inhibit NLRP3 inflammasome activation,” Karin said. “But at the time we didn’t have a good way to induce mitophagy. There were existing drugs that block IL-1 β, but not IL-18.”
In the more recent research, Sanchez-Lopez was studying how macrophages—white blood cells that clean the body of unwanted microscopic particles like bacteria and dead cells—were able to regulate their uptake of the metabolic nutrient choline. Through that inquiry, she identified an inhibitor of the enzyme choline kinase (ChoK), which triggered mitophagy early on—and which they believed could also inhibit the NLRP3 inflammasome.
“When studying how macrophages regulate their uptake of choline, a nutrient critical to metabolism, we came across something that can initiate mitophagy: an inhibitor of the enzyme choline kinase (ChoK), that blocks the incorporation of choline into mitochondrial membranes,” explains Sanchez-Lopez. “As a result, the cells perceive mitochondria as damaged, and cleared them away by mitophagy, therefore inhibiting NLRP3 inflammasome activation.”
By testing the process in mice, UCSD found that treatment with ChoK inhibitors prevented acute inflammation caused by uric acid, bacterial toxins and even some specific genetic mutations. As one example, a mutation in the NLRP3 gene is known to cause Muckle-Well syndrome, in which hyperactive cryopyrin proteins lead to inappropriate inflammatory response causing fever, rash, painful and swollen joints, and cell damage. While mice impacted by Muckle-Well syndrome usually present with a spleen nearly twice as large as normal mice, the research team found that following ChoK inhibitor treatment, the spleen size returned to normal. Of particular interest here is that this represents a novel way to inhibit IL-18, with the promise of more options to come.
“We are planning to test the efficacy of choline kinase inhibitors in a number of IL-1β- and IL-18-dependent diseases, especially lupus nephritis, osteoarthritis, Alzheimer’s disease and cardiac infarction,” says Sanchez-Lopez. “We also found another potential target, the choline transporter CTL1, which is induced in macrophages during inflammation. We found that genetic ablation of the CTL1 in macrophages also effectively induces mitophagy and reduces NLRP3 inflammasome activation. Unfortunately, CTL1-specific blockers are not yet available.”
The UCSD team intends to collaborate with medicinal formulators to improve the design of current ChoK inhibitors and develop CTL1 blockers. While the efficacy of ChoK inhibitors is currently being evaluated in Phase 1 clinical trials for the treatment of solid advanced tumors, full data isn’t yet available. Because of the risk of side effects, they will need to proceed with a full evaluation of all impacts of ChoK inhibitors before any clinical utilization.
“Currently, the majority of the ChoK inhibitors are developed from choline analog Hemocholinium, which at high doses might affect the synthesis of the neurotransmitter acetylcholine,” warns Sanchez-Lopez. “For this reason, rational design of new non-choline based ChoK inhibitors is of utmost importance. In addition, the design of specific blockers of CTL1 may provide another alternative therapeutic strategy to shut down NLRP3-dependent inflammation.”