Jurnal Internasional Mekanisme pensinyalan yang menginduksi hiporesponsivenitas fagosit selama peradangan sistemik
MRP alarmins induce IL-10-dependent monocyte responsiveness -, STAT-3–, and BCL after cardiopulmonary bypass surgery.
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Responsive phagocyte inflammation against exogenous and endogenous stimuli is strictly regulated. This regulation plays an important role in systemic inflammatory response syndrome (SIRS). In SIRSs, phagocytes initially develop a hyperinflammatory response, followed by a secondary state of hyporesponsiveness, called “tolerance.” This hyporesponsiveness can be induced by stimulation of endotoxins from Toll-like receptor 4 (TLR4), resulting in an improved response after subsequent restimulation. Modification of the pattern of this inflammatory response has been described as innate immune memory. Interestingly, tolerance can also be triggered by endogenous TLR4 ligands, such as alarmins related to myeloid 8 proteins (MRP8, S100A8) and MRP14 (S100A9), in sterile conditions. However, the signaling pathway that triggers phagocyte hyporesponsiveness in clinically relevant diseases is only difficult to understand. Through our work, we have now identified 2 main signaling cascades activated during MRP-induced phagocytic tolerance. We show that the phosphatidylinositol 3-kinase / AKT / GSK-3β pathway interferes with the expression of NF-κB-driven genes and that inhibition of tolerance mimics GSK-3β in vivo. In addition, we identified interleukin-10 which triggered activation of the STAT3 and BCL-3 transcription factors as the main regulator of MRP-induced tolerance. Thus, patients with dominant-negative STAT3 mutations do not show developmental tolerance. In clinically relevant conditions with systemic sterile stress, cardiopulmonary bypass surgery, we confirm the initial induction of MRP expression and monocyte tolerance induction associated with STAT3 and BCL-3 nuclear translocation as relevant mechanisms. Our data suggest that the use of pharmacological JAK-STAT inhibitors can be a promising target for future therapeutic approaches to prevent complications associated with secondary hyporesponsivity during SIRS.
- Submitted February 26 2019.
- Accepted April 30, 2019.
- © 2019 by The American Society of Hematology