Blockade of MIF biological activity ameliorates house dust mite‐induced allergic airway inflammation in humanized MIF mice

• Published in: The FASEB journal Vol. 37; no. 8; pp. e23072 - n/a
• Main Authors: Dunbar, Hazel, Hawthorne, Ian J., Tunstead, Courteney, Armstrong, Michelle E., Donnelly, Seamas C., English, Karen
• Format: Journal Article
• Language: English
• Published: United States 01.08.2023
• Subjects: airway inflammation; Airway Remodeling; allergic asthma; Animals; Asthma; Disease Models, Animal; house dust mite; Humans; Inflammation - metabolism; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - metabolism; Lung - metabolism; macrophage migration inhibitory factor; Macrophage Migration-Inhibitory Factors - genetics; Macrophage Migration-Inhibitory Factors - metabolism; Mice; MIF; MIF inhibitors; Pyroglyphidae; severe asthma; airway inflammation; allergic asthma; house dust mite; macrophage migration inhibitory factor; airway remodeling; severe asthma; MIF; MIF inhibitors
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202300787R

Macrophage migration inhibitory factor (MIF) expression is controlled by a functional promoter polymorphism, where the number of tetranucleotide repeats (CATTn) corresponds to the level of MIF expression. To examine the role of this polymorphism in a pre‐clinical model of allergic asthma, novel humanized MIF mice with increasing CATT repeats (CATT5 and CATT7) were used to generate a physiologically relevant scale of airway inflammation following house dust mite (HDM) challenge. CATT7 mice expressing high levels of human MIF developed an aggressive asthma phenotype following HDM challenge with significantly elevated levels of immune cell infiltration, production of inflammatory mediators, goblet cell hyperplasia, subepithelial collagen deposition, and airway resistance compared to wild‐type controls. Importantly the potent MIF inhibitor SCD‐19 significantly mitigated the pathophysiology observed in CATT7 mice after HDM challenge, demonstrating the fundamental role of endogenous human MIF expression in the severity of airway inflammation in vivo. Up to now, there are limited reproducible in vivo models of asthma airway remodeling. Current asthma medications are focused on reducing the acute inflammatory response but have limited effects on airway remodeling. Here, we present a reproducible pre‐clinical model that capitulates asthma airway remodeling and suggests that in addition to having pro‐inflammatory effects MIF may play a role in driving airway remodeling. CATT7 and WT mice received HDM challenge, which enters through the damaged epithelium resulting in an increase in goblet cell hyperplasia, airway remodeling, eosinophilia, cellular infiltration, Th2 cytokine production, and airway resistance. High human MIF expressing CATT7 mice present a more severe phenotype compared to WT mice. By blocking MIF's active site, MIF inhibitor SCD‐19 decreases these hallmark signs in CATT7 mice. No change is seen in WT mice. Created using Biorender.com.