Abstract
Critical illness and sepsis are characterized by drastic changes in the systemic innate immune response, particularly involving monocytes. The exact monocyte activation profile during sepsis, however, has remained obscure. Therefore, we prospectively analyzed the gene expression profile of circulating CD14+ monocytes from healthy volunteers (n = 54) and intensive care unit (ICU) patients (n = 76), of which n = 36 had sepsis. RNA sequencing of selected samples revealed that monocytes from septic ICU patients display a peculiar activation pattern, which resembles characteristic functional stages of monocyte-derived macrophages and is distinct from controls or non-sepsis ICU patients. Focusing on 55 highly variable genes selected for further investigation, arachidonate 5-lipoxygenase-activating protein (ALOX5AP) was highly upregulated in monocytes of ICU patients and only normalized during 7 days in the ICU in non-sepsis patients. Strikingly, low monocytic guanine nucleotide exchange factor 10-like protein (ARHGEF10L) mRNA expression was associated with the disease severity and mortality of ICU patients. Collectively, our comprehensive analysis of circulating monocytes in critically ill patients revealed a distinct activation pattern, particularly in ICU patients with sepsis. The association with disease severity, the longitudinal recovery or lack thereof during the ICU stay, and the association with prognosis indicate the clinical relevance of monocytic gene expression profiles during sepsis.
Highlights
Sepsis is a leading cause of death worldwide
In a prospective study comprising more than 100 critically ill patients admitted to the intensive care unit (ICU), we recently demonstrated a significant increase in total leukocyte numbers in the peripheral blood of ICU patients compared to healthy volunteers and patients with infections from a standard care unit
We found a clear correlation between the APACHE II score for ICU patients and ALOX5AP mRNA expression (r = 0.4253, p = 0.0032; Figure 7C), supporting its association with disease severity
Summary
Sepsis is a leading cause of death worldwide. It often manifests as a complex immune dysfunction where a hyper-inflammatory reaction, the “cytokine storm”, simultaneously occurs alongside an insufficient (“hypo”) immune reaction [1,2]. Low serum 25-hydroxyvitamin D levels have been shown to impact the outcome of critically ill patients with sepsis [8,9]. Reliable biomarkers provide at least two major advances in the difficult clinical management of sepsis: early recognition and differential etiological diagnosis. MiR-15a and miR-16 are upregulated in the serum of neonatal sepsis patients [12] and, have been shown to be useful to distinguish patients with sepsis from those with systemic inflammatory response syndrome (SIRS) [13]. Other microRNAs, such as miR-133a, might even have predictive power in the setting of critical illness [14]
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