Signaling mechanisms inducing hyporesponsiveness of phagocytes during systemic inflammation

The inflammatory responsiveness of phagocytes to exogenous and endogenous stimuli is tightly regulated. This regulation plays an important role in systemic inflammatory response syndromes (SIRSs). In SIRSs, phagocytes initially develop a hyperinflammatory response, followed by a secondary state of hyporesponsiveness, a so-called "tolerance." This hyporesponsiveness can be induced by endotoxin stimulation of Toll-like receptor 4 (TLR4), resulting in an ameliorated response after subsequent restimulation. This modification of inflammatory response patterns has been described as innate immune memory. Interestingly, tolerance can also be triggered by endogenous TLR4 ligands, such as the alarmins myeloid-related protein 8 (MRP8, S100A8) and MRP14 (S100A9), under sterile conditions. However, signaling pathways that trigger hyporesponsiveness of phagocytes in clinically relevant diseases are only barely understood. Through our work, we have now identified 2 main signaling cascades that are activated during MRP-induced tolerance of phagocytes. We demonstrate that the phosphatidylinositol 3-kinase/AKT/GSK-3β pathway interferes with NF-B–driven gene expression and that inhibition of GSK-3β mimics tolerance in vivo. Moreover, we identified interleukin-10–triggered activation of transcription factors STAT3 and BCL-3 as master regulators of MRP-induced tolerance. Accordingly, patients with dominant-negative STAT3 mutations show no tolerance development. In a clinical...

Source: Blood - July 10, 2019 Category: Hematology Authors: Freise, N., Burghard, A., Ortkras, T., Daber, N., Imam Chasan, A., Jauch, S.-L., Fehler, O., Hillebrand, J., Schakaki, M., Rojas, J., Grimbacher, B., Vogl, T., Hoffmeier, A., Martens, S., Roth, J., Austermann, J. Tags: Immunobiology and Immunotherapy, Phagocytes, Granulocytes, and Myelopoiesis Source Type: research