MIF antagonism restores corticosteroid sensitivity in a murine model of severe asthma

Abstract

Introduction: Currently there are no available therapies for the treatment of severe corticosteroid-resistant neutrophilic asthma. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that regulates neutrophil recruitment to sites of inflammation. It also overrides the anti-inflammatory activity of corticosteroids. Aim: To determine whether combined treatment with the MIF antagonist ISO-1 and the corticosteroid dexamethasone inhibits neutrophilic inflammation in a murine model of severe corticosteroid resistant asthma. Methods: Female C57BL/6 mice (N = 9-18) were sensitized subcutaneously with house dust mite (HDM) (100µg) emulsified in Complete Freund’s adjuvant or PBS on day 0. ISO-1(35mg/kg) and dexamethasone (Dex, 1mg/kg), either alone or in combination, were administered 30 min prior to HDM challenge on day 14. Airway inflammation and airway hyperreactivity (AHR), measured using forced oscillation technique, was assessed the following day. Results: HDM induced a significant increase of MIF in the BALF, a mixed eosinophilic/neutrophilic response, and AHR. Dex significantly reduced eosinophil numbers and AHR, but had no effect on the neutrophilic response. ISO-1 had no effect on airway inflammation or AHR. However, combined treatment with ISO-1 and Dex led to a significant reduction in neutrophil numbers, and further inhibited AHR. Conclusion: MIF antagonism restores corticosteroid sensitivity in severe asthma.