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Inhibition of macrophage migration inhibitory factor ameliorates ocular Pseudomonas aeruginosa-induced keratitis
Mihaela Gadjeva1, Jill Nagashima, Tanweer Zaidi
1Department of Medicine, Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America. mgadjeva@rics.bwh.harvard.edu
Abstract:
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.
Insights
Macrophage migration inhibitory factor (MIF) exacerbates Pseudomonas aeruginosa keratitis by increasing inflammation and bacterial invasion. Inhibiting MIF reduces corneal damage and improves outcomes in this sight-threatening infection.
Area of Science:
- Ophthalmology
- Immunology
- Microbiology
Background:
- Pseudomonas aeruginosa keratitis is a severe corneal infection leading to vision loss.
- Inflammation is the primary driver of corneal damage and visual acuity loss in P. aeruginosa infections.
Purpose of the Study:
- To investigate the role of macrophage migration inhibitory factor (MIF) in P. aeruginosa keratitis.
- To evaluate the therapeutic potential of targeting MIF in corneal infections.
Main Methods:
- Comparison of P. aeruginosa keratitis outcomes in MIF-deficient (knockout) mice versus wild-type mice.
- Administration of recombinant MIF and a MIF inhibitor to assess their effects on infection severity and pathology.
- Analysis of bacterial clearance, neutrophil infiltration, inflammatory mediator synthesis, and epithelial cell invasion.
Main Results:
- MIF-deficient mice exhibited significantly reduced corneal pathology, improved bacterial clearance, and decreased inflammation compared to wild-type mice.
- Reintroducing MIF restored disease severity in deficient mice, confirming MIF's essential role.
- MIF inhibition ameliorated disease-associated pathology.
- MIF enhanced corneal epithelial cell responses, increasing pro-inflammatory mediator synthesis and promoting bacterial invasion.
Conclusions:
- Macrophage migration inhibitory factor (MIF) is a critical host factor that promotes P. aeruginosa virulence and corneal pathology.
- MIF inhibition represents a potential therapeutic strategy for managing sight-threatening P. aeruginosa keratitis.
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