Comparison of Inflammation, Organ Damage, and Oxidant Stress Induced by Salmonella enterica Serovar Muenchen Flagellin and Serovar Enteritidis Lipopolysaccharide

Abstract

Gram-negative sepsis is related to the activation of interconnected inflammatory cascades in response to bacteria and their products. Recent work showed that flagellin, the monomeric subunit of bacterial flagella, triggers innate immune responses mediated by Toll-like receptor 5. Here, we compared the effects of Salmonella enterica serovar Enteritidis lipopolysaccharide (LPS) and recombinant Salmonella enterica serovar Muenchen flagellin administered intravenously (100 g) to mice. Flagellin and LPS both elicited a prototypical systemic inflammatory response, with increased levels of tumor necrosis factor alpha, gamma interferon, interleukin 6 and 10, and nitrate in plasma. Flagellin induced a widespread oxidative stress, evidenced by an increase in malondialdehyde and a decrease in reduced glutathione in most organs, as well as liver (increased plasma aminotransferases), but not renal, injury. Alternatively, LPS resulted in a less severe oxidative stress and triggered renal, but not liver, damage. Sequestration of polymorphonuclear neutrophils (increased myeloperoxidase activity) in the lungs was observed with both toxins, while only LPS recruited neutrophils in the gut. In additional experiments, the simultaneous administration of small doses of LPS and flagellin (10 g) induced a synergistic enhancement of the production of proinflammatory cytokines. Our data support a novel concept implicating flagellin as a mediator of systemic inflammation, oxidant stress, and organ damage induced by gram-negative bacteria.

Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice

“…21 The flagellin-TLR5 axis might also trigger cardiac innate immune responses and result in cardiovascular dysfunction. 22 Consistent with previous reports, 23,24 we previously demonstrated that either intranasally or intraperitoneally administered flagellin could induce a significant increase in the serum aminotransferase levels in mice, 25 suggesting that flagellin might be a potent inducer of liver damage. Flagellin-triggered responses exert various effects on different cells, tissues and organs; these responses vary greatly according to the dose, physiological condition of the cell, the animal used and the experimental setting.…”

“…High-dose flagellin induced acute liver function abnormality, damage and oxidative stress As reported previously, 23,24 flagellin induced widespread systemic inflammation and significant increase in aminotransferase…”

“…For example, the intravenous injection of 100 mg flagellin/mouse induced liver damage, as determined by increased serum ALT/AST levels. 23 An additional study did not observe the same side effects using 25-50 mg/mouse. 16 This is one reason why we analyzed the dose-dependent effects of flagellin on the development of liver injury in mice and tested doses of 0-200 mg.…”

“…Because flagellin is linked to a wide range of diseases and might induce significant liver damage based on our observations 25 and those of other studies, 23,27 flagellin might be an essential determinant of liver injury. However, flagellin can also activate the inflammasome NLRC4 pathway in addition to TLR5 signaling.…”

Deletion of Flagellin’s Hypervariable Region Abrogates Antibody-Mediated Neutralization and Systemic Activation of TLR5-Dependent Immunity

“…We and others have shown that i.v. injection of flagellins promotes a systemic response, characterized by the production of proinflammatory mediators (such as TNF-␣ or IL-6) and DC activation (5,6,(13)(14)(15)(16)(17). Furthermore, flagellins trigger mucosa-specific innate and adaptive defense mechanisms (18 -20).…”