Abstract
The systemic inflammatory response syndrome (SIRS) is a potentially lethal response triggered by diverse forms of tissue injury and infection. When systemic inflammation is triggered by infection, the term sepsis is used. Understanding how inflammation is mediated and regulated is of enormous medical importance. We previously demonstrated that circulating inflammatory-relevant microRNAs (CIR-miRNAs) are candidate biomarkers for differentiating sepsis from SIRS. Here, we set out to determine how CIR-miRNA levels reflect SIRS severity and whether they derive from activated immune cells. Clinical disease severity scores and markers of red blood cell (RBC) damage or immune cell activation were correlated with CIR-miRNA levels in patients with SIRS and sepsis. The release of CIR-miRNAs modulated during SIRS was assessed in immune cell cultures. We show that severity of non-infective SIRS, but not sepsis is reflected in the levels of miR-378a-3p, miR-30a-5p, miR-30d-5p, and miR-192-5p. These CIR-miRNA levels positively correlate with levels of the redox biomarker, peroxiredoxin-1 (Prdx-1), which has previously been shown to be released by immune cells during inflammation. Furthermore, in vitro activated immune cells produce SIRS-associated miR-378a-3p, miR-30a-5p, miR-30d-5p, and miR-192-5p. Our study furthers the understanding of the origin, role, and trafficking of CIR-miRNAs as potential regulators of inflammation.
Highlights
The systemic inflammatory response syndrome [SIRS [1]] can be triggered by diverse forms of injury including burns, ischemia, autoimmune diseases, injuries including surgery and infection
To determine whether CIR-miRNA levels are regulated by the severity of SIRS, crossing point (Cp) of single miRNAs were compared to the mean Cp of internal normalizers [as previously identified [35]] to give dCp values that increase with the abundancy of specific miRNAs
CIR-miRNAs positively correlate with levels of the inflammatory mediator and redox enzyme, Prdx-1 which is released by immune cells in inflammation
Summary
The systemic inflammatory response syndrome [SIRS [1]] can be triggered by diverse forms of injury including burns, ischemia, autoimmune diseases, injuries including surgery and infection. Even with optimal medical care, mortality rates in severe sepsis increase to around 50% [3] In this respect, clinical scores, such as the sequential organ failure assessment [SOFA [4]] and the acute physiology and chronic health evaluation II [APACHE II [5]], are useful to evaluate SIRS severity and patient mortality risk. Damage- and/or pathogen-associated molecular pattern molecules (respectively, DAMPs and PAMPs) released after injury (or infection) initiate, via toll-like receptor (TLR) signals [6, 8], an activation cascade in immune and endothelial cells leading to inflammatory cytokine production [e.g., tumor necrosis factor (TNF) α, IL-1, IL-6, and IL-8], in a so-called “cytokine storm” [9, 10]. Understanding the responses which occur in noninfective inflammation and sepsis and how they are regulated will aid development of diagnostics and therapeutics in these major inflammatory diseases
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