Homotrimeric Macrophage Migration Inhibitory Factor (MIF) Drives Inflammatory Responses in the Corneal Epithelium by Promoting Caveolin-rich Platform Assembly in Response to Infection
Authors
Thomas Reidy, Alexander Rittenberg, Markryan Dwyer, Samantha D’Ortona, Gerald Pier, and Mihaela Gadjeva
Institution
Harvard Medical School
Year
2013
Journal
JBC
Abstract
Acute inflammation that arises during Pseudomonas aeruginosa-
induced ocular infection can trigger tissue damage resulting
in long term impairment of visual function, suggesting that
the appropriate treatment strategy should include the use of
anti-inflammatory agents in addition to antibiotics.Werecently
identified a potential target for modulation during ocular infection,
macrophage migration inhibitory factor (MIF). MIF deficiency
protected mice from inflammatory-mediated corneal
damage resulting from acute bacterial keratitis. To gain a better
understanding of the molecular mechanisms of MIF activity, we
analyzed the oligomeric states and functional properties of MIF
during infection. We found that in human primary corneal cells
infected with P. aeruginosa, MIF is primarily in a homotrimeric
state. Homotrimeric MIF levels correlated with the severity of
infection in the corneas of infected mice, suggesting that the
MIF homotrimers were the functionally active form of MIF.
During infection, human primary corneal cells released more
IL-8 when treated with recombinant, locked MIF trimers than
when treated with lower MIF oligomers. MIF promoted
P. aeruginosa–induced IL-8 responses via the formation of
caveolin-1-rich “signaling hubs” in the corneal cells that led to
elevatedMAPKp42/p44 activation and sustained inflammatory
signaling. These findings suggest that inhibiting homotrimerization
of MIF or the functional activities of MIF homotrimers
could have therapeutic benefits during ocular inflammation.