Inhibition of macrophage migration inhibitory factor ameliorates ocular Pseudomonas aeruginosa-induced keratitis.
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.
Gadjeva
Mihaela
M
Department of Medicine, Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America. mgadjeva@rics.bwh.harvard.edu
Nagashima
Jill
J
Zaidi
Tanweer
T
Mitchell
Robert A
RA
Pier
Gerald B
GB
D000818:Animals; D004195:Disease Models, Animal; D019573:Epithelium, Corneal / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D005260:Female; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D007634:Keratitis / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D011743:Pyrimidines / Q000494:pharmacology*; D034741:RNA, Small Interfering
C532251:4-iodo-6-phenylpyrimidine; D008263:Macrophage Migration-Inhibitory Factors; D011743:Pyrimidines; D034741:RNA, Small Interfering; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse