Inhibition of Macrophage Migration Inhibitory Factor Ameliorates Ocular Pseudomonas aeruginosa-Induced Keratitis

PLoS Pathogens

Tanweer Zaidi¹  Jill Nagashima¹  Gerald B. Pier¹  Mihaela Gadjeva¹  Robert A. Mitchell² 

[1] Department of Medicine, Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America;James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, United States of America

关键词: Pseudomonas aeruginosa;    Cornea;    Epithelial cells;    Eye diseases;    Inflammation;    Eyes;    Small interfering RNAs;    Keratitis;   

DOI  :  10.1371/journal.ppat.1000826

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Pseudomonas aeruginosa causes severe sight-threatening corneal infections, with the inflammatory response to the pathogen being the major factor resulting in damage to the cornea that leads to loss of visual acuity. We found that mice deficient for macrophage migration inhibitory factor (MIF), a key regulator of inflammation, had significantly reduced consequences from acute P. aeruginosa keratitis. This improvement in the outcome was manifested as improved bacterial clearance, decreased neutrophil infiltration, and decreased inflammatory responses when P. aeruginosa-infected MIF knock out (KO) mice were compared to infected wild-type mice. Recombinant MIF applied to infected corneas restored the susceptibility of MIF deficient mice to P. aeruginosa-induced disease, demonstrating that MIF is necessary and sufficient to cause significant pathology at this immune privileged site. A MIF inhibitor administered during P. aeruginosa-induced infection ameliorated the disease-associated pathology. MIF regulated epithelial cell responses to infection by enhancing synthesis of proinflammatory mediators in response to P. aeruginosa infection and by promoting bacterial invasion of corneal epithelial cells, a correlate of virulence in the keratitis model. Our results uncover a host factor that elevates inflammation and propagates bacterial cellular invasion, and further suggest that inhibition of MIF during infection may have a beneficial therapeutic effect.

【 授权许可】

CC BY