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Published on: July 26, 2017
Differential expression of Toll-like receptor (TLR)-2 and TLR-4 on monocytes in human sepsis
L Armstrong1, A R L Medford, K J Hunter
1Lung Research Group, University of Bristol Division of Medicine, Southmead Hospital, Bristol, UK. lynne.armstrong@bris.ac.uk
Abstract:
Toll-like receptors (TLRs) are a recently described family of immune receptors involved in the recognition of pathogen-associated molecular patterns (PAMPs). The central role of TLR-2 and TLR-4 in microbial responses suggests they may be implicated in the pathogenesis of human sepsis. We hypothesized that the incidence and outcome of sepsis would be influenced by the expression of TLR-2 and TLR-4 on monocytes. We have examined the expression of TLR-2 and TLR-4 mRNA and protein and their response to pro- and anti-inflammatory agents on monocytes from subjects in the intensive therapy unit (ITU) with and without Gram-negative, Gram-positive or polymicrobial sepsis. We compared these data to ITU and healthy control subjects. TLR-2 mRNA was significantly up-regulated on monocytes from subjects with both Gram-positive and Gram-negative sepsis. Similarly, we detected increased levels of TLR-2 protein on the surface of monocytes from sepsis subjects relative to ITU controls. TLR-4 mRNA was increased in Gram-positive subjects; however, there was no corresponding increase in TLR-4 protein. Although TLR-4 mRNA expression in healthy control monocytes could be modulated in vitro by culture with lipopolysaccharide or interleukin-10, this was not observed in monocytes obtained from sepsis and ITU control subjects, suggesting that septic and ITU control milieus may alter the immunoregulation of TLR-4 mRNA expression on monocytes. TLR-2 mRNA was not modulated in culture by any stimulus in any group. We suggest that expression and regulatory response of monocyte TLR-2, and to a lesser extent TLR-4 may be abnormal in human sepsis.
Insights
Monocyte Toll-like receptors (TLRs), crucial for pathogen recognition, show altered expression in sepsis patients. This suggests abnormal TLR-2 and TLR-4 regulation may contribute to sepsis pathogenesis and outcomes.
Area of Science:
- Immunology
- Molecular Biology
- Critical Care Medicine
Background:
- Toll-like receptors (TLRs) are key immune receptors recognizing pathogen-associated molecular patterns (PAMPs).
- TLR-2 and TLR-4 play central roles in microbial responses, implicating them in sepsis pathogenesis.
- Monocyte TLR expression may influence sepsis incidence and outcomes.
Purpose of the Study:
- To investigate the expression and regulation of TLR-2 and TLR-4 on monocytes in patients with sepsis.
- To compare monocyte TLR expression in sepsis patients with intensive therapy unit (ITU) and healthy controls.
Main Methods:
- Examined TLR-2 and TLR-4 mRNA and protein expression on monocytes.
- Assessed monocyte response to pro- and anti-inflammatory agents in vitro.
- Compared monocytes from sepsis patients, ITU controls, and healthy controls.
Main Results:
- TLR-2 mRNA and protein were significantly upregulated on monocytes from sepsis patients (Gram-positive and Gram-negative).
- TLR-4 mRNA increased in Gram-positive sepsis, but protein levels did not correlate.
- Monocytes from sepsis and ITU controls showed impaired in vitro regulation of TLR-4 mRNA, unlike healthy controls.
Conclusions:
- Monocyte TLR-2 expression and regulatory responses appear abnormal in human sepsis.
- TLR-4 expression and regulation may also be altered in the septic milieu.
- These findings suggest a potential role for monocyte TLRs in sepsis pathophysiology.
