β-Hydroxybutyrate attenuates bronchial smooth muscle proinflammatory cytokine production and contraction

Asthma is a chronic respiratory condition characterized by airway inflammation, remodeling, and hyperresponsiveness to triggers that lead to airway constriction and impaired airflow. Bronchial smooth muscle (BSM) plays a central role in these processes by constricting the airways and producing proinflammatory cytokines in response to environmental triggers, allergens, and cytokines. Although current therapies, including bronchodilators, corticosteroids, and biologics, effectively treat many patients, additional strategies are needed for difficult-to-treat asthma. Emerging evidence suggests that therapeutic ketosis, achieved through dietary interventions or exogenous ketone supplementation, may reduce airway hyperresponsiveness and inflammation. Classically known as metabolic fuels, ketone bodies also signal through cell-surface receptors and transporters to elicit their activities. Increased ketone body levels in vivo, such as during weight loss or caloric restriction, correlate with improved asthma symptoms, reduced oxidative stress, and decreased inflammation. Here, we investigated the predominant ketone body, β-hydroxybutyrate (BHB), as a potential modulator of BSM function. Using human bronchial smooth muscle cells in vitro, we found that BHB suppresses IL-1β-induced proinflammatory cytokine production and attenuates histamine-induced contraction through a mechanism involving activation of the free fatty acid receptor 3 (FFAR3). In mouse precision-cut lung slices (PCLS) ex vivo, we demonstrated that both BHB and an FFAR3 agonist reduce histamine-induced airway narrowing and epithelial cellular extrusion. Collectively, these findings identify BSM and FFAR3 as cellular targets of therapeutic ketosis and support BHB as a potential beneficial agent for mitigating inflammation and bronchoconstriction in asthma.NEW & NOTEWORTHY Asthma is characterized by airway inflammation and bronchoconstriction, with aberrant bronchial smooth muscle function contributing to disease severity. Therapeutic ketosis, achieved through a ketogenic diet or exogenous ketone supplementation, attenuates airway inflammation and bronchial hyperresponsiveness. Using bronchial smooth muscle cells and precision-cut lung slices, we demonstrate that the ketone body β-hydroxybutyrate (BHB) suppresses IL-1β-induced proinflammatory cytokine production and histamine-evoked bronchoconstriction via activation of the free fatty acid receptor FFAR3.