There is a continuing need for alternative treatment options for a substantial proportion of patients with respiratory disorders such as asthma and chronic obstructive pulmonary disease. Writing in Science Translational Medicine, teams led by Brightling, Milligan and Tobin report that agonists of free fatty acid receptor 4 (FFA4) can dampen asthma-like symptoms in mice, indicating its potential as a novel therapeutic target.
FFA4 is a G protein-coupled receptor (GPCR) expressed in the gut and pancreas, where it is activated by a range of free circulating long-chain fatty acids. Its involvement in regulating glucose homeostasis has previously been a focus of drug discovery efforts. However, recent studies have reported abundant expression of FFA4 in lung epithelial cells, suggesting that it might also be a target for respiratory diseases.
To confirm the activity of FFA4 in the airway epithelium, the authors used two well-characterized agonists, TUG-891 and the more specific TUG-1197. Treatment of lung slices from wild-type mice with the two ligands resulted in activation of the Gq11/phospholipase C/inositol phosphate signal transduction pathway downstream of FFA4, and in a rapid increase in intracellular calcium. This led to airway smooth muscle (ASM) relaxation in airways that had been precontracted with carbachol or serotonin, an effect that was surprising because elevation of calcium in ASM generally causes contraction rather than relaxation. This effect was indeed mediated by FFA4, since lung slices derived from Ffa4-knock-out mice showed no calcium response to TUG-1197.
Next, the authors evaluated the ability of FFA4 agonists to restore normal lung function in mouse models of acute and chronic ozone pollution, and in mouse models of inflammatory airway disease induced by cigarette smoke or house dust mites. In these models activation of FFA4 reduced airway resistance, returning lung function to near normal.
Activation of FFA4 with TUG-891 and TUG-1197 resulted in ASM relaxation even in the presence of an already established inflammatory lung disease. Milligan had hoped to see anti-inflammatory activity, and indeed, the compounds had an anti-inflammatory effect, with a reduction in the number of infiltrated neutrophils and macrophages. Finally, TUG-891 also relaxed lung tissue taken from healthy humans and precontracted with acetylcholine, supporting the relevance of the findings for potential progression of FFA4 modulators into clinical trials for respiratory diseases.
“Better and certainly more potent ligands will be needed. It will be interesting to see if companies that worked extensively on FFA4 in the context of glucose homeostasis and diabetes — but were never able to bring a compound targeting this receptor to clinical trials — might re-examine their chemistry programmes with this different indication in mind,” concludes Milligan.
Nature Reviews Drug Discovery 19, 672 (2020)