Caveolin-1-Deficient Mice Show Defects in Innate Immunity and Inflammatory Immune Response during Salmonella enterica Serovar Typhimurium Infection

• DOI: 10.1128/iai.00949-06
• Publication Date: 2006-11-21T01:05:37Z
• Authors: Freddy A. Medina; Cecilia J. de Alm...; Elliott Dew; Jiangwei Li; Gloria Bonuccelli; Terence M. Williams; Alex W. Cohen; Richard G. Pestell; Philippe G. Frank; Herbert B. Tanowitz; Michael P. Lisanti
• Keywords: Lipopolysaccharides; Mice, Knockout; STAT3 Transcription Factor; Salmonella typhimurium; 0301 basic medicine; Granuloma; Neutrophils; Macrophages; Caveolin 1; Nitric Oxide; Immunity, Innate; 3. Good health; Mice; 03 medical and health sciences; Liver; Salmonella Infections; Animals; Cytokines; Spleen

ABSTRACT

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.