3 research outputs found
Alarmins MRP8 and MRP14 Induce Stress Tolerance in Phagocytes under Sterile Inflammatory Conditions
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
Alarmins MRP8 and MRP14 Induce Stress Tolerance in Phagocytes under Sterile Inflammatory Conditions
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
Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases
Background: Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a
distinct autoinflammatory entity involving extremely high serum
concentrations of the proinflammatory alarmin myeloid-related protein
(MRP) 8/14 (S100A8/S100A9 and calprotectin).
Objective: We sought to characterize the genetic cause and clinical
spectrum of Hz/Hc.
Methods: Proline-serine-threonine phosphatase-interacting protein 1
(PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and
their clinical phenotype was compared with that of 11 patients with
pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome.
PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation
and Western blotting. A structural model of the PSTPIP1 dimer was
generated. Cytokine profiles were analyzed by using the multiplex
immunoassay, and MRP8/14 serum concentrations were analyzed by using an
ELISA.
Results: Thirteen patients were heterozygous for a missense mutation in
the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a
mutation resulting in p. E257K. Both mutations substantially alter the
electrostatic potential of the PSTPIP1 dimer model in a region critical
for protein-protein interaction. Patients with Hz/Hc have extremely high
MRP8/14 concentrations (2045 +/- 1300 mu g/mL) compared with those with
PAPA syndrome (116 +/- 74 mu g/mL) and have a distinct clinical
phenotype. A specific cytokine profile is associated with Hz/Hc. Hz/Hc
mutations altered protein binding of PSTPIP1, increasing interaction
with pyrin through phosphorylation of PSTPIP1.
Conclusion: Mutations resulting in charge reversal in the y-domain of
PSTPIP1 (E -> K) and increased interaction with pyrin cause a distinct
autoinflammatory disorder defined by clinical and biochemical features
not found in patients with PAPA syndrome, indicating a unique
genotype-phenotype correlation for mutations in the PSTPIP1 gene. This
is the first inborn autoinflammatory syndrome in which inflammation is
driven by uncontrolled release of members of the alarmin family