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Signaling mechanisms inducing hypo-responsiveness of phagocytes during systemic inflammation

Nicole Freise, Alina Burghard, Theresa Ortkras, Niklas Daber, Achmet Imam Chasan, Saskia-L. Jauch, Olesja Fehler, Julia Hillebrand, Mosab Schakaki, Jessica Rojas, Bodo Grimbacher, Thomas Vogl, Andreas Hoffmeier, Sven Martens, Johannes Roth and Judith Austermann

Key Points

  • MRP alarmins induce an IL-10-, STAT-3- and BCL-3-dependent hypo-responsiveness of monocytes after cardiopulmonary bypass surgery.

Abstract

The inflammatory responsiveness of phagocytes to exogenous and endogenous stimuli is tightly regulated. This regulation plays an important role in systemic inflammatory response syndromes (SIRS). In SIRS phagocytes initially develop a hyper-inflammatory response followed by a secondary state of hypo-responsiveness, a so called tolerance. This hypo-responsiveness can be induced by endotoxin stimulation of Toll-like receptor 4 (TLR4) resulting in an ameliorated response after subsequent re-stimulation. 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 alarmins MRP8 (myeloid-related protein) and MRP14, under sterile conditions. However, signaling pathways that trigger hypo-responsiveness of phagocytes in clinically relevant diseases are only barely understood. Through our work, we have now identified two main signaling cascades that are activated during MRP-induced tolerance of phagocytes. We demonstrate that the PI3K/AKT/GSK-3β pathway interferes with NF-kB-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 clinically relevant condition of systemic sterile stress, cardiopulmonary bypass surgery, we confirmed the initial induction of MRP-expression and the tolerance induction of monocytes associated with nuclear translocation of STAT3 and BCL-3 as relevant mechanisms. Our data indicate that the use of pharmacological JAK-STAT inhibitors may be promising targets for future therapeutic approaches to prevent complications associated with secondary hypo-responsiveness during SIRS.

  • Submitted February 26, 2019.
  • Revision received April 30, 2019.
  • Accepted April 30, 2019.