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Double-Mutant Mice Resist Septic Arthritis but Display Increased Mortality in Response to Staphylococcus aureus1
*
Department of Rheumatology, University of Göteborg, Göteborg, Sweden;
Section of Clinical Immunology, University Hospital Zurich, Switzerland;
Centenary Institute of Cancer Medicine and Cell Biology, Sydney, Australia; and
§
Institute for Neurobiology, Hygiene and Immunology, Erlangen, Germany
To evaluate the importance of the proinflammatory cytokines TNF and
lymphotoxin-
(LT) in an experimental model of
Staphylococcus aureus sepsis and arthritis, we used
TNF/LT-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 x
107/mouse) resulted in 67% mortality in
TNF/LT-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/LT. Thus,
at day 6 after inoculation, S. aureus could not be found
in the bloodstream of controls, but bacteremia developed in all
TNF/LT-deficient mice examined (p = 0.02).
Interestingly, upon infection with a lower dose of staphylococci
(3 x 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/LT-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/LT-deficient mice as compared with wild-type
counterparts. Our results show the importance of TNF/LT 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.
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