Toll-like receptor 4 expression on circulating leucocytes in hemolytic uremic syndrome

Abstract

Lipopolysaccharide stimulation of toll-like receptor 4 (TLR4) activates signal transduction pathways leading to proinflammatory cytokine secretion. We investigated TLR4 surface receptor expression on peripheral blood neutrophils and monocytes and their ability to modulate inflammatory cytokine release in 15 patients 1, 3, and 10 days after hemolytic uremic syndrome (HUS) onset. Seven patients with Escherichia coli (EHEC)-associated diarrhea and seven healthy controls were also studied. Isolated leucocytes from HUS-onset patients exhibited significantly higher messenger RNA (mRNA) TLR4 expression than controls. Moreover, TLR4 protein expression on neutrophils, determined by flow cytometry, was upregulated, driving dependent proinflammatory cytokine, tumor necrosis factor alpha (TNF-α), and interleukin 8 (IL-8) increase, and decreased anti-inflammatory IL-10 release at HUS onset compared with patients with EHEC diarrhea and controls. TLR4 expression on neutrophils was positively correlated with serum TNF-α levels. Conversely, significant reduction of neutrophil TLR4 receptor expression and lack of cytokine-responsive element activation was shown in patients 3 and 10 days after HUS onset. No differences were demonstrated in TLR4 receptor expression on monocytes among the studied groups. Our results suggest TLR4 expression may be differently regulated on neutrophils and monocytes. They could be dynamically modulated across the early development of HUS on neutrophils, resulting in negative regulation preceded by TLR4 overactivation.

Identification of TLR4 as the Receptor That Recognizes Shiga Toxins in Human Neutrophils

“…Because TLR4 expression increases after exposure to LPS or proinflammatory cytokines (60), one possible explanation for this discrepancy is that the known degranulating effect induced by Stx on human neutrophils (78) can rapidly enhance the surface exposure of TLR4 (79). In line with our hypothesis, TLR4 cell-surface expression in circulating neutrophils greatly increased in patients with HUS within 24 h of disease diagnosis, whereas TLR4 membrane expression did not change in circulating monocytes (80).…”

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