Hyporesponsiveness by phagocytes, a well-known phenomenon in sepsis, 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 myeloid-related protein (MRP) 8 and MRP14 induce phagocyte hyporesponsiveness via chromatin modifications in a TLR4-dependent manner resulting in enhanced survival during murine septic shock. Also during sterile inflammation, polytrauma and burn patients present with initially high MRP serum concentrations identifying these proteins as obvious candidates for triggering secondary hyporesponsiveness in these patients. Interestingly, increased peripartal MRP concentrations prime human neonatal phagocytes for hyporesponsiveness, which was confirmed in murine neonatal endotoxinemia in wildtype and MRP14 -/- mice. Using a comparative bioinformatics analysis between genome-wide response patterns of MRP- and LPS- tolerized monocytes we demonstrated no difference in global gene expression between samples pretreated with either MRP8-MRP14 or LPS. Our data indicate that alarmin-triggered phagocyte tolerance represents a novel regulatory mechanism for the susceptibility of neonates to systemic infections and during sterile inflammation.

Human blood monocytes prestimulated with MRP8-MRP14 or LPS and afterwards activated with LPS were selected for RNA extraction and hybridization on Illumina microarrays.

Lipopolysaccharide and MRP8-MRP14 exposure (2021 ICD-10-CM code* = Not Applicable)

The data were normalised using quantile normalisation in Partek Genomic Suite

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE61477