title: Role of Toll-like receptors 2, 4, and 9 in mediating neutrophil dysfunction in alcoholic hepatitis.
abstract: Neutrophil dysfunction in alcoholic hepatitis is associated with endotoxemia and an increased incidence of infection, but the mechanism is unclear. We aimed to investigate the role of Toll-like-receptors (TLR)2, 4, and 9 in mediating neutrophil dysfunction in alcoholic hepatitis. Neutrophils from healthy volunteers were incubated with alcoholic hepatitis patients' plasma (n = 12) with and without TLR2, 4, or 9 antagonists and with and without human albumin. TLR2, 4, and 9 expression, neutrophil oxidative burst, phagocytosis, and CXCR1+2 expression were measured by FACS analysis. Patients' plasma increased oxidative burst, decreased CXCR1+2 expression, and decreased phagocytosis of normal neutrophils in association with increased expression of TLR2, 4, and 9 and depletion of ATP. Inhibition of TLR2, 4, and 9 prevented the increase in oxidative burst and the decrease in CXCR1 and CXCR2 expression but did not prevent phagocytic dysfunction. Incubation with albumin completely prevented the patient plasma induced neutrophil dysfunction. Increased expression of TLR2, 4, and 9 is associated with neutrophil dysfunction, endotoxemia, and energy depletion. TLR2, 4, and 9 inhibition does not improve phagocytosis, indicating that TLR overexpression may be the result and not the cause of neutrophil activation. Albumin, an endotoxin scavenger, prevents the deleterious effect of patients' plasma on neutrophil phagocytosis, resting burst, and TLR expression.
authors.affiliation: Institute of Hepatology, UCL Medical School, 68-75 Chenies Mews, London WC1E 6H, UK.
authors.forename: V
authors.initials: V
authors.lastname: Stadlbauer
authors.forename: R P
authors.initials: RP
authors.lastname: Mookerjee
authors.forename: G A K
authors.initials: GA
authors.lastname: Wright
authors.forename: N A
authors.initials: NA
authors.lastname: Davies
authors.forename: G
authors.initials: G
authors.lastname: Jürgens
authors.forename: S
authors.initials: S
authors.lastname: Hallström
authors.forename: R
authors.initials: R
authors.lastname: Jalan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D006519:Hepatitis, Alcoholic / Q000097:blood / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology*; D010587:Phagocytosis; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D016897:Respiratory Burst; D012709:Serum Albumin / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000032:analysis; D051197:Toll-Like Receptor 4 / Q000032:analysis; D051217:Toll-Like Receptor 9 / Q000032:analysis; D051193:Toll-Like Receptors / Q000032:analysis*
chemical_list: D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D012709:Serum Albumin; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D000255:Adenosine Triphosphate