Vanderbilt Health researchers have identified FFAR3, a cell membrane receptor that can “reprogram” inflammatory immune cells, as a potential drug target for treating asthma.
Their findings, reported in the journal Nature Communications, suggest that a drug which activates FFAR3 could bring relief to the more than 26 million people in the United States with asthma, a chronic and complex inflammatory disease of the airways.
FFAR3 (free fatty acid receptor 3) is a G protein-coupled receptor, a member of a family of membrane-bound proteins through which hormones, neurotransmitters, and more than half of all drugs exert their effects.
The discovery of FFAR3’s potential to reduce inflammation by reprogramming specific immune cells in the lung is a scientific tour de force that applied cutting-edge gene mapping techniques to a panel of laboratory mice, called the Collaborative Cross, which encompasses an exceptionally broad spectrum of genetic variation.
“Targeting a free fatty acid receptor to treat asthma is a true paradigm shift in the strategy to treat these diseases,” said Stokes Peebles, MD, the Elizabeth and John Murray Professor of Medicine and the paper’s co-corresponding author with Mark Rusznak, PhD, an MD/PhD student in his lab.
The Collaborative Cross is an international effort to enhance quantitative trait locus (QTL) and systems genetic analyses in mice. QTLs are regions of DNA associated with observable biological traits that result from multiple genes interacting with the environment.
By combining founder strains of laboratory mice to create more than 60 recombinant inbred strains, the Collaborative Cross enables researchers to scan an unprecedented range of gene expression for disease-relevant targets that otherwise might be missed in studies limited to a single mouse strain.
“The Collaborative Cross is a revolutionary laboratory mouse resource that allows scientists to understand the genetics behind complex diseases,” Rusznak said. “We used this resource to identify a gene that acts as an inflammatory switch in an immune cell that plays a major role in asthma.”
The Peebles lab investigates mechanisms regulating pulmonary inflammation in allergen-induced and virus-mediated disease. This study focused on ILC2s, innate lymphoid (white blood) cells that initiate inflammatory responses in the lung.
After inducing inflammation in the mouse lung in a way that mirrored what occurs during allergen-exacerbated asthma in humans, the researchers used QTL mapping to identify a locus, or DNA region, associated with the regulation of the inflammatory ILC2 response.
By comparing different mouse strains, they identified a strain that produced ILC2s with reduced inflammatory potential. Then they looked for ILC2-regulating genes in the newly mapped locus that also were expressed in humans, and which could be targeted with drugs.
That led to the gene for FFAR3. In the gastrointestinal tract, FFAR3 stimulates the release of leptin, a peptide hormone that plays a role in appetite suppression. The receptor also is involved in insulin secretion and in regulating heart rate and blood pressure.
Adding an agent that stimulated FFAR3 activation in mouse and human ILC2s grown in culture increased the number of cells that had a diminished capacity to produce inflammatory cytokines (signaling molecules). This suggests that FFAR3 can “reprogram” ILC2s from their normally inflammatory state to an anti-inflammatory one.
“The ability of activating FFAR3 to decrease the function of group 2 innate lymphoid cells (ILC2) was completely unexpected, but the data is very clear,” Peebles said. “ILC2 cells produce cytokines that initiate and potentiate allergic inflammation, the driving force behind diseases such as allergic rhinitis and asthma.”
“Our findings are exciting for the field of asthma research,” added Rusznak, the paper’s first author, who designed the experiments, analyzed the data and wrote the manuscript.
While further study is needed before an FFAR3-based redirection of the inflammatory pathway in asthma can be tested in humans, “we hope that our work provides a proof of concept for using the Collaborative Cross to find human-relevant genetic targets in many other diseases,” he said.
Researchers from the University of North Carolina at Chapel Hill, Indiana University and the University of Iowa contributed to the study.
Other co-authors currently at Vanderbilt Health are Shinji Toki, PhD, Weisong Zhou, PhD, Masako Abney, MA, Matthew Stier, MD, PhD, Christopher Thomas, Jing Li, Andrew Pahnke, Mark Petrovic, Jacqueline Cephus, MS, Shelby Kuehnle, Wade Calcutt, PhD, Fang Yan, MD, PhD, Jeremy Goettel, PhD, and Dawn Newcomb, PhD.
The study was supported in part by National Institutes of Health grants R01AI124456, R01AI145265, U19AI095227, R01AI111820, R21AI145397, and F30AI176712, and by the Department of Veterans Affairs.
