Improved Innate Immunity of Endotoxin-Tolerant Mice Increases Resistance toSalmonella entericaSerovar Typhimurium Infection despite Attenuated Cytokine Response

Abstract

During infection with gram-negative bacteria, exposure of immune cells to lipopolysaccharide (LPS) from the bacterial cell membrane induces a rapid cytokine response which is essential for the activation of host defenses against the invading pathogens. Administration of LPS to mice induces a state of hyporesponsiveness, or tolerance, characterized by reduced cytokine production upon subsequent LPS challenge. In the model of experimental Salmonella enterica serovar Typhimurium infection of mice, we assessed the question of whether complete LPS tolerance induced by repetitive doses of LPS interfered with cytokine production and host defense against gram-negative bacteria. Although production of various cytokines in response to serovar Typhimurium was attenuated by LPS pretreatment, LPS-tolerant mice showed improved antibacterial activity, evidenced by a prolongation of survival and a continuously lower bacterial load. We attribute this protective effect to three independent mechanisms. (i) Peritoneal accumulation of leukocytes in the course of LPS pretreatment accounted for enhanced defense against serovar Typhimurium during the first 6 h of infection but not for decreased bacterial load in late-stage infection. (ii) LPS-tolerant mice had an increased capacity to recruit neutrophilic granulocytes during infection. (iii) LPS-tolerant mice showed threefold-increased Kupffer cell numbers, enhanced phagocytic activity of the liver, and strongly improved clearance of blood-borne serovar Typhimurium. These results demonstrate that despite attenuated cytokine response, acquired LPS tolerance is associated with enhanced resistance to infections by gram-negative bacteria and that this effect is mainly mediated by improved effector functions of the innate immune system. Endotoxin, or lipopolysaccharide (LPS), a glycolipid of the cell membranes of gram-negative bacteria, is one of the most potent stimulators of immune responses known. The immune system responds to LPS with a systemic production of proinflammatory cytokines, which recruit and activate immune cells to eliminate invading pathogens (40). Although these cytokines are indispensible for the efficient control of the growth and dissemination of the pathogen (7,10,17), an excessive inflammatory response is potentially autodestructive and may lead to microcirculatory dysfunction, causing tissue damage, septic shock, and eventually death (3, 14). The phenomenon of endotoxin tolerance is known from animal models of "sterile infection" induced by LPS: after an initial low dose of LPS, animals are protected against the detrimental consequences of a subsequent high dose of LPS. This protection is associated with an attenuated cytokine response to LPS (11) due to a downregulation of macrophage responsiveness (12).The value of endotoxin tolerance induction as a mean of sepsis prophylaxis was studied in animal models of endotoxic shock or polymicrobial sepsis. In these models, protection by tolerance induction was ascribed to the decreased proinflammatory response, resulting i...

NLRP1 and NLRP3 inflammasomes are essential for distinct outcomes of decreased cytokines but enhanced bacterial killing upon chronic Nod2 stimulation

“…Chronic MDP treatment did not affect cell viability or S. typhimurium uptake (data not shown). Bacterial killing differences of these magnitudes are seen following PRR ligand and cytokine stimulation of macrophages and other cells (7,24,32,49,52) and can, in some cases, contribute to dramatic differences in survival and disease susceptibility (49,52,55,56). Leu1007insC Nod2 homozygote/compound heterozygote MDM show trends toward decreased S. typhimurium clearance, even at baseline (Fig.…”

Cellular Mechanisms That Cause Suppressed Gamma Interferon Secretion in Endotoxin-Tolerant Mice

“…Some investigators have postulated that the suppressed cytokine response observed in the tolerant host will result in impaired antimicrobial immunity. However, recent reports have shown that LPS-tolerant mice are more resistant to systemic infection with Cryptococcus neoformans or Salmonella enterica serovar Typhimurium (19,28). LPS tolerance has clinical relevance because the changes in immune function observed in this model parallel those seen following sepsis, major trauma, thermal injury, and high-risk surgery (1,2,8).…”

Induction of Long-Term Lipopolysaccharide Tolerance by an Agonistic Monoclonal Antibody to the Toll-Like Receptor 4/MD-2 Complex

“…It has been reported that LPS pretreatment improves the clearance of bacteria and fungi in infection experiments (14,20) and increases survival in cecal ligation and puncture-induced sepsis (5,24) and in colon ascendens stent peritonitis (7). Therefore, it is highly expected that UT12 will result in FIG.…”

“…This phenomenon is called LPS tolerance and is defined as the reduced capacity of the host or cultured macrophage/monocyte to respond to LPS following initial stimulation (6,26). It has also been reported that bacterial or fungal removal is improved during the tolerant state, despite attenuated cytokine production (14,20). Therefore, LPS tolerance is regarded as a reasonable response that simultaneously manages both the clearance of pathogens and host protection from excess inflammation.…”