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Alarmins MRP8 and MRP14 induce stress tolerance in phagocytes under sterile inflammatory conditions
Judith Austermann1, Judith Friesenhagen2, Selina Kathleen Fassl3
1Institute of Immunology, University of Münster, 48149 Münster, Germany; Interdisciplinary Centre for Clinical Research, University of Münster, 48149 Münster, Germany.
Abstract:
Hyporesponsiveness by phagocytes is a well-known phenomenon in sepsis that is frequently induced by low-dose endotoxin stimulation of Toll-like receptor 4 (TLR4) but can also be found under sterile inflammatory conditions. We now demonstrate that the endogenous alarmins MRP8 and MRP14 induce phagocyte hyporesponsiveness via chromatin modifications in a TLR4-dependent manner that results in enhanced survival to septic shock in mice. During sterile inflammation, polytrauma and burn trauma patients initially present with high serum concentrations of myeloid-related proteins (MRPs). Human neonatal phagocytes are primed for hyporesponsiveness by increased peripartal MRP concentrations, which was confirmed in murine neonatal endotoxinemia in wild-type and MRP14(-/-) mice. Our data therefore indicate that alarmin-triggered phagocyte tolerance represents a regulatory mechanism for the susceptibility of neonates during systemic infections and sterile inflammation.
Insights
Endogenous alarmins, myeloid-related proteins (MRPs), induce phagocyte hyporesponsiveness through chromatin changes, enhancing survival in septic shock models. This alarmin-triggered tolerance impacts neonatal susceptibility to infections and inflammation.
Area of Science:
- Immunology
- Molecular Biology
- Pathophysiology
Background:
- Phagocyte hyporesponsiveness is a known issue in sepsis, often triggered by Toll-like receptor 4 (TLR4) activation.
- This phenomenon also occurs during sterile inflammatory conditions.
Purpose of the Study:
- To investigate the role of endogenous alarmins, specifically myeloid-related proteins (MRPs) MRP8 and MRP14, in inducing phagocyte hyporesponsiveness.
- To determine if this alarmin-induced hyporesponsiveness affects survival in a septic shock model.
Main Methods:
- Demonstrated alarmin-induced hyporesponsiveness via TLR4-dependent chromatin modifications.
- Assessed survival rates in mice subjected to septic shock.
- Measured serum MRP concentrations in trauma patients and in murine models of neonatal endotoxemia.
Main Results:
- Endogenous alarmins MRP8 and MRP14 induce phagocyte hyporesponsiveness through TLR4-dependent chromatin modifications.
- This hyporesponsiveness led to enhanced survival in mice challenged with septic shock.
- High serum MRP concentrations were observed in trauma patients and in neonatal endotoxemia models.
Conclusions:
- Alarmin-triggered phagocyte tolerance is a regulatory mechanism.
- This mechanism influences the susceptibility of neonates to systemic infections and sterile inflammation.
- MRPs play a critical role in modulating immune responses during inflammation and infection.
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