Lanthionine synthetase C-like receptors reduce eosinophilia, type 2 immune responses and lung inflammatory pathology in mouse models of asthma

Airway hyperresponsiveness and asthma are associated with altered glucose metabolism with inhibition of anaerobic glycolysis reducing inflammation and lung eosinophilia. LANCL receptors are key focal points for metabolism in immune cells, controlling mitochondrial mass and oxidative pathways all while promoting immunoregulatory differentiation. Knockout of LANCL receptors leads to diminished Treg differentiation, altered epithelial cell metabolism and impaired phagocytic clearance, all of which can contribute to the chronicity of asthma. We developed an oral agonist for LANCL receptors and tested it within ovalbumin and house dust mite induced models of asthma in mice. Treatment in vitro with the agonist resulted in reduced differentiation of inflammatory and allergic CD4+ T cells and reduced production of inflammatory cytokines in macrophages. In the OVA model, oral treatment with an LANCL therapeutic, beginning on the second day of aerosol challenge significantly reduced neutrophilia and eosinophilia in the lung by flow cytometry and histology. LANCL treatment significantly reduced anti-OVA IgE titers and type 2 cytokines, IL-5 and IL-13. Reduction of eosinophilia and type 2 immune responses were validated in the house dust mite model. In both models, lung gene expression trends were consistent with improved pulmonary function and mitochondrial metabolism. Thus, activation of LANCL receptors is a feasible strategy for the treatment of asthma and pulmonary inflammation.