Macrophage migration inhibitory factor enhances Pseudomonas aeruginosa biofilm formation, potentially contributing to cystic fibrosis pathogenesis

• Published in: The FASEB journal Vol. 31; no. 11; p. 5102
• Main Authors: Tynan, Aisling, Mawhinney, Leona, Armstrong, Michelle E, O'Reilly, Ciaran, Kennedy, Sarah, Caraher, Emma, Jülicher, Karen, O'Dwyer, David, Maher, Lewena, Schaffer, Kirsten, Fabre, Aurélie, McKone, Edward F, Leng, Lin, Bucala, Richard, Bernhagen, Jürgen, Cooke, Gordon, Donnelly, Seamas C
• Format: Journal Article
• Language: English
• Published: United States 01.11.2017
• Subjects: Animals; Biofilms - growth & development; Cystic Fibrosis - drug therapy; Cystic Fibrosis - metabolism; Cystic Fibrosis - microbiology; Disease Models, Animal; Intramolecular Oxidoreductases - metabolism; Intramolecular Oxidoreductases - pharmacology; Macrophage Migration-Inhibitory Factors - metabolism; Macrophage Migration-Inhibitory Factors - pharmacology; Mice; Pseudomonas aeruginosa - physiology; Recombinant Proteins - pharmacology; Tobramycin - pharmacology; cytokine; bacteria; respiratory infections
• ISSN: 1530-6860
• DOI: 10.1096/fj.201700463R

Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator that we have previously shown to be associated with an aggressive clinical phenotype in cystic fibrosis. It possesses unique tautomerase enzymatic activity. However, to date, no human-derived substrate has been identified that has the capacity to interact with this cytokine's unique tautomerase activity. This led us to hypothesize that MIF may have the capacity to interact with external substrates. We describe for the first time how can utilize human recombinant MIF (rMIF) to significantly ( < 0.01) enhance its endogenous biofilm formation. Our studies demonstrate that utilizing a small-molecular-weight inhibitor targeting MIF's tautomerase activity (SCD-19) significantly reduces the inflammatory response in a murine pulmonary chronic model. In addition, we show that in experiments, pretreatment of with rMIF is associated with reduced bacterial killing by tobramycin. Our novel findings support the concept of an anti-MIF strategy that targets this enzymatic activity as a potential future antibacterial therapeutic approach.-Tynan, A., Mawhinney, L., Armstrong, M. E., O'Reilly, C., Kennedy, S., Caraher, E., Jülicher, K., O'Dwyer, D., Maher, L., Schaffer, K., Fabre, A., McKone, E. F., Leng, L., Bucala, R., Bernhagen, J., Cooke, G., Donnelly, S. C. Macrophage migration inhibitory factor enhances biofilm formation, potentially contributing to cystic fibrosis pathogenesis.