Alarmins MRP8 and MRP14 Induce Stress Tolerance in Phagocytes under Sterile Inflammatory Conditions

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.

Ubiquitin Urine Levels in Burn Patients

“…Systemic ubiquitin levels are elevated in various diseases, such as sepsis, trauma, burns or myocardial infarction (22). We have shown previously that serum ubiquitin concentrations correlate with the burn size in patients, which is in agreement with the passive release of damage-associated molecular patterns (DAMP) from damaged cells and tissues after burns (22, 32–36). In contrast to systemic levels of the prototypical DAMPs high mobility group box 1 (HMGB1) and S100A8/9 after burns, however, we observed that patients who develop multiple organ failure or die have a relative deficiency of serum ubiquitin during the first week after injury (32, 33, 36).…”

“…We have shown previously that serum ubiquitin concentrations correlate with the burn size in patients, which is in agreement with the passive release of damage-associated molecular patterns (DAMP) from damaged cells and tissues after burns (22, 32–36). In contrast to systemic levels of the prototypical DAMPs high mobility group box 1 (HMGB1) and S100A8/9 after burns, however, we observed that patients who develop multiple organ failure or die have a relative deficiency of serum ubiquitin during the first week after injury (32, 33, 36). In combination with the anti-inflammatory and beneficial effects of ubiquitin treatment that have been observed in multiple animal models and species (37–43), these data suggest a protective function of endogenous ubiquitin in the systemic circulation.…”

S100A8 promotes migration and infiltration of inflammatory cells in acute anterior uveitis

“…S100A8/S100A9 proteins are produced intracellularly in granulocytes and monocytes, and then released extracellularly. Extracellular S100A8/S100A9 is thought to influence multiple steps in the leukocyte-recruitment process via binding to surface receptors including Toll-like receptor-4 (TLR4)1217 and the receptor of advanced glycation endproducts (RAGE)13. This results in the induction of proinflammatory cytokine secretion via activation of transcription factor NF-kB181920.…”

Alarmins and Antitumor Immunity

“…[7][8][9][10][11][12] A property common to all alarmins is their capacity to promote inflammation and immunity; however, they are sensed by distinct receptors and have distinct roles. [13][14][15][16][17] With progress in immunology, the functions of alarmins have been further elucidated and their potential clinical use has attracted more research enthusiasm.…”