Bench-to-bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis

Abstract

Endotoxin tolerance is defined as a reduced responsiveness to a lipopolysaccharide (LPS) challenge following a first encounter with endotoxin. Endotoxin tolerance protects against a lethal challenge of LPS and prevents infection and ischemia-reperfusion damage. Endotoxin tolerance is paralleled by a dramatic reduction of tumor necrosis factor (TNF) production and some other cytokines in response to LPS. Endotoxin tolerance involves the participation of macrophages and mediators, such as glucocorticoids, prostaglandins, IL-10, and transforming growth factor-beta. Endotoxin tolerance is accompanied by the up-regulation of inhibitory molecules that down-regulate the Toll-like receptor (TLR)4-dependent signaling pathway. Cross-tolerance between LPS and other TLR specific ligands, as well as IL-1 and TNF, has been regularly reported. A similar loss of LPS reactivity has been repeatedly reported in circulating leukocytes of septic patients and in patients with non-infectious systemic inflammation response syndrome (SIRS). Studies on cellular signaling within leukocytes from septic and SIRS patients reveal numerous alterations reminiscent of those observed in endotoxin tolerant cells. However, altered responsiveness to LPS of leukocytes from sepsis and SIRS patients is not synonymous with a global down-regulation of cellular reactivity. The term 'cellular reprogramming', which has been proposed to qualify the process of endotoxin tolerance, defines well the immune status of circulating leukocytes in septic and SIRS patients.

Figure 1

Inhibitory signals of the Toll-like receptor (TLR)4-induced MyD88-dependent signaling pathway. In addition to negative signals delivered by cytokines, cell surface receptors and numerous intracellular molecules down-regulate the TLR4-dependent signaling pathways following its activation by endotoxin (lipopolysaccharide (LPS)) (see text for further explanation). Small downwards and upwards arrows in squares indicate the down- or up-regulation, respectively, of the compound observed in endotoxin tolerant cells. Framed names of inhibitors indicate their demonstrated involvement in the endotoxin tolerance process. ABIN, A20 binding inhibitor of NF-κB activation; DUSP-1, dual specificity phosphatase 1; Erk, extracellular signal-related kinase; HO-1, heme oxygenase-1; IκB, inhibitor of κB; IRAK, IL-1 receptor associated kinase; MAPK, mitogen-activated protein kinase; MKP, MAPK phosphatase; MyD88, myeloid differentiation 88; NF-κB, nuclear factor-kappa B; pi3K, phosphatidylinositol 3-kinase; SHIP, SH1-containing inositol-5' phosphatase; SIGIRR, single immunoglobulin IL-1R-related molecule; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription; TAK1, TGFβ activating kinase 1; TGF, transforming growth factor; Tollip, Toll interacting protein; TRAF, TNF receptor associated factor.