Abstract
Pattern recognition receptors are a key component of the first line host defense against infection, recognizing specific microbial products. We hypothesize that monocyte hyporesponsiveness in human sepsis is associated with a downregulation of the pattern recognition receptors Toll-like receptor (TLR)-2 and TLR4.Protein expression of CD14, TLR2 and TLR4 on blood monocytes was examined using flow cytometry from 29 patients with sepsis and 14 healthy controls. In addition LPS stimulated TNF-α and IL-10 production was studied in a 24 hour whole blood assay.We found an increased expression of CD14, TLR2 and TLR4 in patients with sepsis compared to controls (p < 0.01). In patients with sepsis, death was associated with significant lower CD14 and TLR2 expression at admission (CD14: 25.7 +- 19.1 vs 39.1 +- 17.3 mean fluorescence intensity [MFI], p = 0.02; TLR2: 21.8 +- 9.4 vs. 30.9 +- 9.6, p = 0.01). At 72 hours the TLR2 expression on monocytes was associated with the IL-10 inducibility after LPS stimulation (r = 0.52, p = 0.02) and the CD14 expression with the IL-6, IL-10 and TNF inducibility.We conclude that septic patients are characterized by an increased expression of CD14, TLR2 and TLR4 on monocytes compared to controls. Death is associated with downregulation of TLR2 and CD14 expression on monocytes correlating with reduced cytokine inducibility. We suggest that CD14 and TLR2 are a key factor in monocyte hyporesponsibility during severe sepsis.
Highlights
Severe sepsis is the cause of 9% to 22% intensive care unit admissions and is associated with a mortality rate up to 50% [1]
We suggest that CD14 and TLR2 are a key factor in monocyte hyporesponsibility during severe sepsis
In murine macrophages TLR4 expression correlates with the inducibility of the proinflammatory response to LPS [10], whereas stimulation with TLR2 agonist has been associated with the rapid release of IL-10 [11]
Summary
Severe sepsis is the cause of 9% to 22% intensive care unit admissions and is associated with a mortality rate up to 50% [1]. Bacterial antigens trigger the initial cytokine response to infection, which is necessary for the clearance of invading pathogens, but overwhelming activation of immune cells, with excessive production of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, is thought to be responsible for the clinical manifestation of septic shock [2,3]. TLR4, together with CD14 and the MD2 adapter molecule, serves as the main receptor for components from gram negative bacteria such as lipopolysaccharide (LPS) [4], whereas TLR2 is crucial to the propagation of the inflammatory response to components mainly from gram-positive organisms, yeast and mycobacteria including lipoteichonic acid (LTA) and lipoarabinomannan [57]. TLR2 is activated by bacterial peptidoglycan, bacterial lipoproteins and lipopeptides, cell wall structures expressed on virtually all clinically relevant gram positive and gram negative bacterial pathogens [8]. In murine macrophages TLR4 expression correlates with the inducibility of the proinflammatory response to LPS [10], whereas stimulation with TLR2 agonist has been associated with the rapid release of IL-10 [11]
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