title: Caveolin-1-deficient mice show defects in innate immunity and inflammatory immune response during Salmonella enterica serovar Typhimurium infection.
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.
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Bluemle Life Sciences Building, Room 933, 233 S. 10th Street, Philadelphia, PA 19107, USA.
authors.forename: Freddy A
authors.initials: FA
authors.lastname: Medina
authors.forename: Cecilia J
authors.initials: CJ
authors.lastname: de Almeida
authors.forename: Elliott
authors.initials: E
authors.lastname: Dew
authors.forename: Jiangwei
authors.initials: J
authors.lastname: Li
authors.forename: Gloria
authors.initials: G
authors.lastname: Bonuccelli
authors.forename: Terence M
authors.initials: TM
authors.lastname: Williams
authors.forename: Alex W
authors.initials: AW
authors.lastname: Cohen
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Frank
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Tanowitz
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D006099:Granuloma / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D007113:Immunity, Innate / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012480:Salmonella Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D012486:Salmonella typhimurium; D013154:Spleen / Q000276:immunology / Q000473:pathology
chemical_list: D051242:Caveolin 1; D016207:Cytokines; D008070:Lipopolysaccharides; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D009569:Nitric Oxide