Endotoxin Priming Improves Clearance ofPseudomonas aeruginosain Wild-Type and Interleukin-10 Knockout Mice

Abstract

Endotoxin (lipopolysaccharide [LPS]) tolerance is an altered state of immunity caused by prior exposure to LPS, in which production of many cytokines, including gamma interferon (IFN-␥) and interleukin-12 (IL-12), are reduced but secretion of the anti-inflammatory cytokine IL-10 is increased in response to a subsequent LPS challenge. This pattern of cytokine production is also characteristic of postinflammatory immunosuppression. Therefore, we hypothesized that LPS-primed mice would exhibit an impaired ability to respond to systemic infection with the opportunistic pathogen Pseudomonas aeruginosa. We further hypothesized that depletion of IL-10 would reverse the endotoxin-tolerant state. To test this hypothesis, systemic clearance of Pseudomonas aeruginosa was measured for LPS-primed wild-type and IL-10-deficient mice. LPS-primed wild-type mice exhibited significant suppression of LPS-induced IFN-␥ and IL-12 but increased IL-10 production in blood and spleen compared to levels exhibited by saline-primed wild-type mice. The suppressed production of IFN-␥ and IL-12 caused by LPS priming was ablated in the spleens, but not blood, of IL-10 knockout mice. LPS-primed wild-type mice cleared Pseudomonas aeruginosa from lungs and blood more effectively than saline-primed mice. LPS-primed IL-10-deficient mice were particularly efficient in clearing Pseudomonas aeruginosa after systemic challenge. These studies show that induction of LPS tolerance enhanced systemic clearance of Pseudomonas aeruginosa and that this effect was augmented by neutralization of IL-10.

RICK Promotes Inflammation and Lethality after Gram-Negative Bacterial Infection in Mice Stimulated with Lipopolysaccharide

“…Furthermore, the expression of TNF-␣ and IL-6 is differentially regulated in response to P. aeruginosa (34). We also found that pretreatment with LPS reduced the loads of P. aeruginosa in tissues in both wild-type and RICK-deficient mice, which is consistent with a previous study (38). In addition, this effect of LPS is similar to that observed when mice are pretreated with lipopeptide which resulted in increased bacterial clearance after infection with Salmonella (32).…”

“…During infection with gram-negative organisms, LPS and other bacterial molecules are released into the blood circulation system, and systemic exposure to these stimuli is known to be harmful to the host (8,9,21). Stimulation of host cells with LPS is known to induce the production of proinflammatory cytokines through the activation of Toll-like receptor 4 (TLR4) and to affect host survival and immune responses to invading gram-negative bacteria (30,38). However, the interplay between TLR4 and other innate signaling pathways in the regulation of proinflammatory responses and host survival after gram-negative infection remains poorly understood.…”

T Cell Ig Mucin-3 Promotes Homeostasis of Sepsis by Negatively Regulating the TLR Response

“…The increased IL-10 expression after Tim-3 blockade in vivo might explain the nonsignificant upregulation of TNF-a in vivo, as IL-10 is known to downregulate TNF-a expression (53). IL-10 is known to be an anti-inflammatory cytokine, but has also been linked to impaired bacterial clearance in sepsis (54), and elevated IL-10 expression in critically ill patients has been correlated with a poor outcome from sepsis (55). Thus, blockade of Tim-3 upregulation of IL-10 expression may not be beneficial but, rather, detrimental.…”

Toll-Like Receptor 2 Ligand Pretreatment Attenuates Retinal Microglial Inflammatory Response but Enhances Phagocytic Activity toward Staphylococcus aureus

“…Thus, ligand-induced tolerance may represent a negative feedback mechanism invoked to induce inflammation resolution and restore homeostasis after TLR activation (28). Preconditioning of animals to TLR ligands such as lipopolysaccharide (LPS) (32,50,56), bacterial lipoproteins (7,16,34), and flagellin (27,28,58) has been shown to provide protection against infection and sepsis in animal models. The retina is extremely sensitive to inflammation-mediated damage (60).…”