Endotoxin tolerance: new mechanisms, molecules and clinical significance

Prior exposure of innate immune cells like monocytes/macrophages to minute amounts of endotoxin cause them to become refractory to subsequent endotoxin challenge, a phenomenon called “endotoxin tolerance”. Clinically, this state is associated with monocytes/macrophages in sepsis patients where they contribute to “immunosuppression” and mortality. The molecular mechanisms underlying endotoxin tolerance remain elusive. The recent appreciation of inflammation as a self-regulating process, the relative contribution of MyD88 versus TRIF signaling pathways in inducing activation or tolerance, plasticity of NF-κB function and the role of chromatin modification and microRNAs in LPS-induced gene reprogramming urges a re-evaluation of endotoxin tolerance. This review integrates these new findings into an up-to-date account of endotoxin tolerance, its molecular basis and clinical implications in different pathologies. Prior exposure of innate immune cells like monocytes/macrophages to minute amounts of endotoxin cause them to become refractory to subsequent endotoxin challenge, a phenomenon called “endotoxin tolerance”. Clinically, this state is associated with monocytes/macrophages in sepsis patients where they contribute to “immunosuppression” and mortality. The molecular mechanisms underlying endotoxin tolerance remain elusive. The recent appreciation of inflammation as a self-regulating process, the relative contribution of MyD88 versus TRIF signaling pathways in inducing activation or tolerance, plasticity of NF-κB function and the role of chromatin modification and microRNAs in LPS-induced gene reprogramming urges a re-evaluation of endotoxin tolerance. This review integrates these new findings into an up-to-date account of endotoxin tolerance, its molecular basis and clinical implications in different pathologies. Acyloxyacyl hydrolase Activating transcription factor 3 B-cell CLL/lymphoma 3 CCAAT/enhancer-binding protein Delta Class II transactivator C-type Lectin domain family 4, member A Cyclooxygenase 2 Dendritic cells Endotoxin tolerance TRAF-type zinc finger domain containing 1(TRAFD1) Formyl peptide receptor 1 Hyaluronic acid High mobility group box 1 proteins Interferon regulatory factor 3 Jun N-terminal kinase Lipopolysaccharide Macrophage-activating lipopeptide Macrophage receptor with collagenous structure Mouse embryonic fibroblasts Major histocompatibility complex Class II Macrophage migration inhibitory factor MAP kinase phosphatase 1 Matrix metalloproteases Myeloid differentation 88 Nuclear factor-kappa B Prostaglandin E2 Poly inositol cytosine Receptor-interacting serine/threonine kinase 1 Ribonucelase T2 SH2-containing Inositol phosphatase Single immunoglobulin IL-IR-related Systemic inflammatory response syndrome Secretory leukoprotease inhibitor Suppressor of cytokine signaling Suppression of tumorigenicity 2 Signal transducer and activator of transcription Tumor-associated macrophages TANK-binding kinase 1 Transforming growth factor, beta Toll-like receptors TNF receptor-associated factor 3 Triggering receptors expressed on myeloid cell 1 TIR domain-containing adapter protein inducing IFN-beta