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.

Deletion of Caveolin-1 Protects against Oxidative Lung Injury via Up-Regulation of Heme Oxygenase-1

“…The cav-1 2/2 mice displayed increased susceptibility to bacterial infection, whereas macrophages derived from these mice exhibited enhanced inflammatory responses to bacterial endotoxin (43). Previously, we have demonstrated an anti-inflammatory function of cav-1 expression in vitro with respect to the inhibition of pro-inflammatory cytokines production during endotoxin-induced inflammation in macrophages (46).…”

“…Recently, cav-1 has also been implicated as a modulator of innate immunity and inflammation (43)(44)(45). The cav-1 2/2 mice displayed increased susceptibility to bacterial infection, whereas macrophages derived from these mice exhibited enhanced inflammatory responses to bacterial endotoxin (43).…”

Molecular Characterization of Caveolin-1 in Pigs Infected with Haemophilus parasuis

“…Caveolin-1 is a key immunomodulatory molecule in the inflammatory response (13,16,67,71), and decreased expression of caveolin-1 in murine alveolar and peritoneal macrophages has a proinflammatory outcome (67). Fibrinous polyserositis is inflammation of the serous tissues with fibrosis.…”

“…However, the pathogenesis of H. parasuis infection remains largely unknown. A recent study demonstrated that caveolin-1 knockout mice were markedly susceptible to Salmonella enterica serovar Typhimurium (13). Whether caveolin-1 is also involved in the pathogenesis of Glasser's disease in pigs is of great interest.…”

“…In humans, caveolin-1 is thought to be a tumor suppressor gene (9)(10)(11)(12). Caveolin-1 knockout mice exhibit defects in innate immunity, such as in the inflammatory response during infection with Salmonella enterica serovar Typhimurium (13) and macrophage phagocytosis (14). In particular, caveolin-1 plays a pivotal role in regulating the inflammatory responses of neutrophils during lung injury (15,16).…”