Pathophysiology of endotoxin tolerance: mechanisms and clinical consequences

Abstract

Endotoxin tolerance was first described in a study that exposed animals to a sublethal dose of bacterial endotoxin. The animals subsequently survived a lethal injection of endotoxin. This refractory state is associated with the innate immune system and, in particular, with monocytes and macrophages, which act as the main participants. Several mechanisms are involved in the control of endotoxin tolerance; however, a full understanding of this phenomenon remains elusive. A number of recent reports indicate that clinical examples of endotoxin tolerance include not only sepsis but also diseases such as cystic fibrosis and acute coronary syndrome. In these pathologies, the risk of new infections correlates with a refractory state. This review integrates the molecular basis and clinical implications of endotoxin tolerance in various pathologies.

The immune response of the human brain to abdominal surgery

“…The depressed ex vivo response to LPS in blood from surgical patients is in line with previously described peripheral immune cell tolerance, typically triggered by anti-inflammatory mediators such as IL-10 and PGE 2 causing dampening of peripheral immune cell reactivity within a duration of up to 5 days after the proinflammatory triggering event. 17,[57][58][59][60] In addition to this autocrine peripheral regulation, there might be an additive neuroimmunological link between the CNS and the peripheral immune system as represented by the cholinergic anti-inflammatory reflex pathway, previously described by Tracey. 61 The analysis of [ 11 C]PBR28 binding and cognitive test data revealed an association between the increase in brain immune activity and an impairment in performance of the highly sensitive Stroop Color-Word Test.…”

Chronic Lymphocytic Leukemia: A Paradigm of Innate Immune Cross-Tolerance

“…Under ET, cells and organisms exhibit a transient, highly tuned state in which they are unable to respond properly to endotoxin challenges (13,14). When uncontrolled, this protective mechanism can become a serious clinical problem, increasing the risk for clinical infection (14).…”

“…In this regard, monocytes play a crucial role in the development and control of ET (13,14). After an ex vivo endotoxin challenge, the monocytes isolated from patients locked into an ET state are unable to orchestrate an inflammatory response, their phagocytic ability increases, and because of the low expression of HLA-II molecules, they show impaired Ag presentation (13)(14)(15). This set of features defines a refractory state (14).…”

“…After an ex vivo endotoxin challenge, the monocytes isolated from patients locked into an ET state are unable to orchestrate an inflammatory response, their phagocytic ability increases, and because of the low expression of HLA-II molecules, they show impaired Ag presentation (13)(14)(15). This set of features defines a refractory state (14). External and internal insults are recognized by the innate immune system, thereby inducing an ET state and subsequently increasing the risk for infection (14).…”

“…This set of features defines a refractory state (14). External and internal insults are recognized by the innate immune system, thereby inducing an ET state and subsequently increasing the risk for infection (14).…”