Background: MIF signals through the MAPK pathway to up-regulate proinflammatory cytokine synthesis. Results: Pseudomonas aeruginosa-induced infection up-regulates MIF homotrimer formation and stimulates assembly of caveolin-1-rich lipid raft, thereby promoting MAPK signaling.
Conclusion:The homotrimeric form of MIF is the functionally active form of the molecule. Significance: The discovery of the functionally active oligomeric form of MIF allows preferential pharmaceutical targeting.
Eye trauma and contact lens wear are the main factors that predispose to the development of infectious keratitis. The existing therapies fail to control the inflammation-driven tissue damage that occurs during Pseudomonas aeruginosa infection. Antibiotic treatment reduces bacterial burdens, but better interventions are needed to alleviate tissue damage resulting from local inflammation. We have previously documented that inhibition of macrophage migration inhibitory factor (MIF) reduces the bacterial levels and the inflammatory damage during keratitis. Here, we report that mice deficient for CD74, the putative MIF receptor, developed milder Pseudomonas aeruginosa-induced disease, characterized by decreased proinflammatory mediators and reduced bacterial presence in the cornea. However, topical inhibition of MIF using antibodies applied to the cornea further promoted recovery from disease, suggesting that in addition to MIF-dependent signaling events, MIF-triggered CD74-independent signaling pathways regulate sensitization to P. aeruginosa-induced infection.
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