Abstract
BackgroundNeonatal sepsis and the associated myocardial dysfunction remain a leading cause of infant mortality. Extracellular cold-inducible RNA-binding protein (eCIRP) acts as a ligand of triggering receptor expressed on myeloid cells-1 (TREM-1). M3 is a small CIRP-derived peptide that inhibits the eCIRP/TREM-1 interaction. We hypothesize that the eCIRP/TREM-1 interaction in cardiomyocytes contributes to sepsis-induced cardiac dysfunction in neonatal sepsis, while M3 is cardioprotective.MethodsSerum was collected from neonates in the Neonatal Intensive Care Unit (NICU). 5–7-day old C57BL/6 mouse pups were used in this study. Primary murine neonatal cardiomyocytes were stimulated with recombinant murine (rm) CIRP with M3. TREM-1 mRNA and supernatant cytokine levels were assayed. Mitochondrial oxidative stress, ROS, and membrane potential were assayed. Neonatal mice were injected with rmCIRP and speckle-tracking echocardiography was conducted to measure cardiac strain. Sepsis was induced by i.p. cecal slurry. Mouse pups were treated with M3 or vehicle. After 16 h, echocardiography was performed followed by euthanasia for tissue analysis. A 7-day survival study was conducted.ResultsSerum eCIRP levels were elevated in septic human neonates. rmCIRP stimulation of cardiomyocytes increased TREM-1 gene expression. Stimulation of cardiomyocytes with rmCIRP upregulated TNF-α and IL-6 in the supernatants, while this upregulation was inhibited by M3. Stimulation of cardiomyocytes with rmCIRP resulted in a reduction in mitochondrial membrane potential (MMP) while M3 treatment returned MMP to near baseline. rmCIRP caused mitochondrial calcium overload; this was inhibited by M3. rmCIRP injection impaired longitudinal and radial cardiac strain. Sepsis resulted in cardiac dysfunction with a reduction in cardiac output and left ventricular end diastolic diameter. Both were improved by M3 treatment. Treatment with M3 attenuated serum, cardiac, and pulmonary levels of pro-inflammatory cytokines compared to vehicle-treated septic neonates. M3 dramatically increased sepsis survival.ConclusionsInhibition of eCIRP/TREM-1 interaction with M3 is cardioprotective, decreases inflammation, and improves survival in neonatal sepsis.Trial registration Retrospectively registered.
Highlights
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection (Singer 2016)
We have previously demonstrated that extracellular Cold-inducible RNA binding-protein (CIRP) is a Damage-associated molecular pattern (DAMP), promoting activation of several cell types including macrophages, lymphocytes, and neutrophils, potentiating cytokine and chemokine production, and propagating formation of neutrophil extracellular traps (NETs) (Qiang 2013; Aziz et al 2019). Extracellular cold-inducible RNA-binding protein (eCIRP) causes endoplasmic reticulum (ER) stress and Nlrp3 inflammasome activation (Yang et al 2016)
Results eCIRP levels are increased in neonates with sepsis Blood samples were obtained from human neonates in the neonatal intensive care unit (NICU) of a tertiary care children’s hospital
Summary
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection (Singer 2016). Sepsis-associated cardiac dysfunction in neonates is not as well studied as in older patients. A recent literature review found that myocardial dysfunction is common with a reported incidence ranging from 10 to 70% (Beesley 2018). This large range is likely due, in part, to the lack of a clinical consensus definition of sepsis-associated cardiac dysfunction (Beesley 2018). We hypothesize that the eCIRP/TREM-1 interaction in cardiomyocytes contributes to sepsis-induced cardiac dysfunction in neonatal sepsis, while M3 is cardioprotective
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