Pharmacological activation of LANCL2 provides immunometabolic protection from disease and lung pathology in mouse models of asthma 2260965

Abstract

Abstract Introduction Asthma is a chronic, complex, immunological disease that afflicts over 28 million people in the U.S. Current therapies are modestly successful but leave significant subpopulations of patients without adequate response. LANCL2 is a novel, immunoregulatory target for the treatment of asthma. Methods The therapeutic efficacy of novel LANCL2-targeting therapeutics was evaluated in the house dust mite (HDM) and ovalbumin (OVA) plus lipopolysaccharide (LPS) models of asthma. For HDM, mice were immunized with an HDM injection and then sensitized intranasally for 3 wk. For OVA+LPS, mice were immunized with OVA, exposed to OVA by aerosolization and then administered LPS intratracheally. Lung immunophenotype, gene expression profiles and histological lesions were evaluated. Expression of inflammatory mediators and key metabolic genes were assessed in human primary bronchial epithelial cells isolated from asthma patients (DHBE) upon pharmacological activation of LANCL2. Results In the HDM model, oral LANCL2 activation decreased lung histopathological lesions, proinflammatory gene expression (CD68, Ifng, Saa3), and the infiltration of neutrophils. In the OVA + LPS model, LANCL2 activation resulted in decreased goblet cell hyperplasia and infiltration of inflammatory immune subsets (IL4+ CD4+ T cells, IL5+ CD11b+ cells and neutrophils) while increasing the proportion of Treg cells in the lungs. In translational studies with DHBE cells, activation of LANCL2 decreased the expression of proinflammatory cytokines Il6 and Tnf, plus Ldha, the glycolytic enzyme that catalyzes the production of lactate. Conclusion Activation of LANCL2 by novel agonists ameliorates disease severity and immunopathology in mouse models of asthma. LANCL2-targeting oral, once-daily small molecule drugs represent innovative approaches for the treatment of neutrophilic asthma. Funding Source N/A Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)