Caveolin-1-Deficient Mice Show Defects in Innate Immunity and Inflammatory Immune Response during Salmonella enterica Serovar Typhimurium Infection
2006
Medina, Freddy A. | de Almeida, Cecilia J. | Dew, Elliott | Li, Jiangwei | Bonuccelli, Gloria | Williams, Terence M. | Cohen, Alex W. | Pestell, Richard G. | Frank, Philippe G. | Tanowitz, Herbert B. | Lisanti, Michael P.
A number of studies have shown an association of pathogens with caveolae. To this date, however, there are no studies showing a role for caveolin-1 in modulating immune responses against pathogens. Interestingly, expression of caveolin-1 has been shown to occur in a regulated manner in immune cells in response to lipopolysaccharide (LPS). Here, we sought to determine the role of caveolin-1 (Cav-1) expression in Salmonella pathogenesis. Cav-1⁻/⁻ mice displayed a significant decrease in survival when challenged with Salmonella enterica serovar Typhimurium. Spleen and tissue burdens were significantly higher in Cav-1⁻/⁻ mice. However, infection of Cav-1⁻/⁻ macrophages with serovar Typhimurium did not result in differences in bacterial invasion. In addition, Cav-1⁻/⁻ mice displayed increased production of inflammatory cytokines, chemokines, and nitric oxide. Regardless of this, Cav-1⁻/⁻ mice were unable to control the systemic infection of SALMONELLA: The increased chemokine production in Cav-1⁻/⁻ mice resulted in greater infiltration of neutrophils into granulomas but did not alter the number of granulomas present. This was accompanied by increased necrosis in the liver. However, Cav-1⁻/⁻ macrophages displayed increased inflammatory responses and increased nitric oxide production in vitro in response to Salmonella LPS. These results show that caveolin-1 plays a key role in regulating anti-inflammatory responses in macrophages. Taken together, these data suggest that the increased production of toxic mediators from macrophages lacking caveolin-1 is likely to be responsible for the marked susceptibility of caveolin-1-deficient mice to S. enterica serovar Typhimurium.
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