Improved innate immunity of endotoxin-tolerant mice increases resistance to Salmonella enterica serovar typhimurium infection despite attenuated cytokine response

During infection with gram-negative bacteria, exposure of immune cells to l ipopolysaccharide (LPS) from the bacterial cell membrane induces a rapid cy tokine response which is essential for the activation of host defenses agai nst the invading pathogens. Administration of LPS to mice induces a state o f hyporesponsiveness, or tolerance, characterized by reduced cytokine produ ction upon subsequent LPS challenge. In the model of experimental Salmonell a enterica serovar Typhimurium infection of mice, we assessed the question of whether complete LPS tolerance induced by repetitive doses of LPS interf ered with cytokine production and host defense against gram-negative bacter ia. Although production of various cytokines in response to serovar Typhimu rium was attenuated by LPS pretreatment, LPS-tolerant mice showed improved antibacterial activity, evidenced by a prolongation of survival and a conti nuously lower bacterial load. We attribute this protective effect to three independent mechanisms. (i) Peritoneal accumulation of leukocytes in the co urse of LPS pretreatment accounted for enhanced defense against serovar Typ himurium during the first 6 h of infection but not for decreased bacterial load in late-stage infection. (iii) LPS-tolerant mice had an increased capa city to recruit neutrophilic granulocytes during infection. (iii) LPS-toler ant mice showed threefold-increased Kupffer cell numbers, enhanced phagocyt ic activity of the liver, and strongly improved clearance of blood-borne se rovar Typhimurium. These results demonstrate that despite attenuated cytoki ne response, acquired LPS tolerance is associated with enhanced resistance to infections by gram-negative bacteria and that this effect is mainly medi ated by improved effector functions of the innate immune system.