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C. G. Hackett, A. Marshak-Rothstein, M. S. Gregory; Both Membrane And Soluble Fas Ligand Are Required For Clearance Of Bacteria And Protection Of Host Tissue During S. aureus Induced Endophthalmitis.. Invest. Ophthalmol. Vis. Sci. 2009;50(13):851.
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© ARVO (1962-2015); The Authors (2016-present)
Endophthalmitis is an infection of the posterior segment of the eye that often results in retinal damage and loss of vision. Fas ligand is required for clearance of bacteria in C57BL/6 mice and our laboratory has shown that, within the eye, membrane FasL is proinflammatory while soluble FasL is anti-inflammatory. We hypothesize that soluble and membrane FasL work together to clear ocular infections; membrane FasL rapidly turns on inflammation to clear the bacteria and soluble FasL turns off inflammation to prevent non-specific retinal damage. To test this we used a novel mutant knock-in mouse that expresses only mFasL and is unable to produce sFasL (ΔCS.1 mice).
ΔCS.1 knock-in mice were created by mutating the FasL cleavage site, preventing formation of sFasL. B6/129-WT and B6/129-ΔCS.1 mice received intravitreal injections of either 500 or 5000 CFU S. aureus (RN6390). Clinical examinations were performed at 24-96 hours post injection. H&E retinal sections were used to assess retinal damage. Neutrophil infiltration was assessed quantitatively using a myeloperoxidase (MPO) assay.
All WT and ΔCS.1 mice successfully cleared a low dose of S. aureus (500 CFU). However, ΔCS.1 mice at 48 hrs post infection displayed increased neutrophil infiltration that coincided with significantly greater retinal damage, as compared with WT mice. This indicates that at low bacterial concentrations, sFasL is critical in preventing prolonged inflammation and non-specific tissue destruction. By contrast, ΔCS.1 mice were more effective at clearing a high concentration of S. aureus (5000 CFU). WT mice cleared 5000 CFU in only 20% of the eyes, while ΔCS.1 mice cleared the same dose in 80% of the eyes.
When a posterior bacterial infection is completely cleared by the host immune response, soluble FasL is critical in limiting non-specific inflammation that damages normal retinal tissue. However, infections of high concentrations of bacteria require expression of mFasL to clear the infection. Therefore, we propose that regulating the ratio of membrane to soluble FasL is essential for maximum bacterial clearance with minimal non-specific tissue damage.
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