TNF/Lymphotoxin-α Double-Mutant Mice Resist Septic Arthritis but Display Increased Mortality in Response toStaphylococcus aureus

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Abstract
To evaluate the importance of the proinflammatory cytokines TNF and lymphotoxin-α (LTα) in an experimental model of Staphylococcus aureus sepsis and arthritis, we used TNF/LTα-double-deficient mice raised on the C57BL/6 background. Mice were i.v. inoculated with a toxic shock syndrome toxin-1 (TSST-1)-producing S. aureus strain, LS-1. Intravenous inoculation of a high dose of bacteria (1 × 107/mouse) resulted in 67% mortality in TNF/LTα-deficient mice, whereas none of the controls died (p = 0.009). Those results correlated to a significantly decreased phagocytosis in vitro and inefficient bacterial clearance in vivo in mice lacking capacity to produce TNF/LTα. Thus, at day 6 after inoculation, S. aureus could not be found in the bloodstream of controls, but bacteremia developed in all TNF/LTα-deficient mice examined (p = 0.02). Interestingly, upon infection with a lower dose of staphylococci (3 × 106/mouse) the mortality was overall low, but the frequency of arthritis was clearly higher in the wild-type group as compared with the TNF/LTα-deficient mice (40% vs 13%). Histopathologic examination revealed a lower frequency of synovitis (38% vs 90%, p < 0.05) and erosivity (25% vs 60%, NS) in TNF/LTα-deficient mice as compared with wild-type counterparts. Our results show the importance of TNF/LTα in defense against systemic S. aureus infections and point out the detrimental role of these cytokines as mediators of inflammatory response in S. aureus arthritis.