Monocyte Subsets Are Differentially Lost from the Circulation during Acute Inflammation Induced by Human Experimental Endotoxemia

Abstract

Three human monocyte subsets are recognized with different functions in the immune system: CD14⁺⁺/CD16^- classical monocytes (CM), CD14⁺⁺/CD16⁺ intermediate monocytes (IM) and CD14⁺/CD16⁺⁺ non-classical monocytes (NCM). Increased IM and NCM percentages have been reported under inflammatory conditions, yet little is known about monocyte subsets at the onset of inflammation. The human endotoxemia model is uniquely capable of studying the first phases of acute inflammation induced by intravenous injection of 2 ng/kg bodyweight lipopolysaccharide (LPS) into healthy volunteers. After that, monocyte subset counts, activation/differentiation status and chemokine levels were studied over 24 h. The numbers of all subsets were decreased by >95% after LPS injection. CM numbers recovered first (3- 6 h), followed by IM (6-8 h) and NCM numbers (8-24 h). Similarly, increased monocyte counts were observed first in CM (8 h), followed by IM and NCM (24 h). Monocytes did not display a clear activated phenotype (minor increase in CD11b and CD38 expression). Plasma levels of CCL2, CCL4 and CX₃CL1 closely resembled the cell numbers of CM, IM and NCM, respectively. Our study provides critical insights into the earliest stages of acute inflammation and emphasizes the necessity to stain for different monocyte subsets when studying the role of monocytes in disease, as neither function nor kinetics of the subsets overlap.

Leukocyte transcriptional signatures dependent on LPS dosage in human endotoxemia

“…In the context of severe infection leading to organ failure (sepsis and septic shock), median levels of systemic LPS levels in patients were estimated at 20 ng/kg . LPS induces substantial alterations to leukocyte cell composition as well as gene transcription . In the early phase of human endotoxemia, monocytes and lymphocytes typically diminish in numbers, whereas neutrophil counts increase dramatically.…”

“…11 LPS induces substantial alterations to leukocyte cell composition as well as gene transcription. 8,9,12,13 In the early phase of human endotoxemia, monocytes and lymphocytes typically diminish in numbers, whereas neutrophil counts increase dramatically. Moreover, LPS induces extensive shifts in leukocyte gene transcription, with genes involved in pro-, anti-inflammatory, pattern recognition, T cell activation signaling, and metabolic pathways typically altered.…”

The Extracellular Matrix: Reloaded Revolutions

“…In their article, Muraleedharan et al provide evidence that conserved miR-183/96/182 clusters can regulate the production of reactive nitrogen and oxygen species in activated macrophages, which may be an alternative option to combat antibiotic-resistant bacterial infections. Apart from microRNAs, the regulation of macrophages can be altered by many other substances, one of them being bacterial lipopolysaccharide (LPS) [17, 18]. CD14 plays an important role in LPS-induced signaling via toll-like receptors.…”

Calibration‐free quantitative immunoassay by flow cytometry: Theoretical consideration and practical implementation for IgG antibody binding to CD14 receptors on human leukocytes

“…Multiple diseases, including bacterial and viral infections, autoimmunity, chronic inflammation and atherosclerosis, are associated with changes in monocyte subsets (23)(24)(25). Significant differences in the behavior of the three monocyte subsets during the early phases of the acute inflammatory response have been revealed (26). The functional response of a cell to a ligand depends on the density of the cell surface receptors (27,28).…”