Immunomodulation by Endotoxin Tolerance in Murine Models of Inflammation and Bacterial Infection

Abstract

Lipopolysaccharide (LPS) is a potent immune stimulator which induces many of the pathological sequelae observed during systemic Gram-negative infection. The term endotoxin tolerance describes the phenomenon that the toxicity of LPS is attenuated upon repeated LPS-stimulation. Selective downregulation of certain macrophage activities is considered one of the mechanisms underlying LPS tolerance. In the present thesis it was investigated whether lipoteichoic acid, a component of Gram-positive bacteria, induced similar tolerance in vivo and macrophage refractoriness in vitro. In the second part of the thesis the effect of acquired LPS tolerance on host defense against virulent bacteria was studied.1. TNF release by murine macrophages in response to lipoteichoic acid (LTA) is independent of Toll like receptor (TLR) 4 but requires functional TLR2.2. LTA induced macrophage refractoriness similar to LPS in vitro and in vivo.3. LTA and LPS induced cross-desensitization of macrophages in vitro and cross-tolerance in galactosamine-sensitized mice in vivo.4. Paracrine mediators did not suffice to induce cross-desensitization of macrophages in vitro.5. Cytokine production in response to viable Salmonella typhimurium was attenuated in LPS-tolerant mice.6. Induction of LPS tolerance prior to Salmonella typhimurium infection was associated with decreased bacterial load and a prolongal of survival.7. Early but not late phase reduction of bacteria in LPS-tolerant mice depended on the accumulation of PMN in the peritoneal cavity in response to intraperitoneal LPS injections.8. LPS-tolerance was associated with increased PMN counts in blood and tissues and enhanced oxidative burst capacity of the individual PMN. Depletion of PMN prior to infection partially abrogated the survival benefit associated with LPS-tolerance.9. LPS-tolerant mice displayed improved clearance of systemically injected Salmonella typhimurium and enhanced phagocytic activity of the liver.