title: Bruton's tyrosine kinase mediates FcγRIIa/Toll-like receptor-4 receptor crosstalk in human neutrophils.
abstract: Previous observations by our laboratory indicate that the presence of anti-IL-8 autoantibody:IL-8 immune complexes in lung fluids from patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) comprises an important prognostic indicator in the development and ultimate outcome of ALI/ARDS. We also showed that these complexes display proinflammatory activity toward neutrophils through the engagement of FcγRIIa receptors. Because sepsis is one of the most common risk factors for ALI/ARDS, the initial goal of our present study involved investigating the effects of LPS on the expression of FcγRIIa receptors in neutrophils. Our results indicate that LPS triggers an increase in the expression of FcγRIIa on the neutrophil surface, which leads to shortening of the molecular distance between FcγRIIa and Toll-like receptor-4 (TLR4). When such neutrophils are stimulated with anti-IL-8:IL-8 complexes, the TLR4 cascade becomes activated via the engagement of FcγRIIa. The underlying molecular mechanism has been subsequently examined and involves Bruton's tyrosine kinase (Btk). In conclusion, our study reveals the existence of Btk-dependent molecular cooperation between FcγRIIa and TLR4 signaling cascades in LPS-"primed" human neutrophils. Furthermore, we used fluorescence lifetime imaging to study the interactions between TLR4 and FcγRIIa in human alveolar neutrophils from patients with ALI/ARDS. The results from these experiments confirm the existence of the molecular cooperation between TLR4 and FcγRIIa.
authors.affiliation: Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Krupa
authors.forename: Rafal
authors.initials: R
authors.lastname: Fudala
authors.forename: Jon M
authors.initials: JM
authors.lastname: Florence
authors.forename: Torry
authors.initials: T
authors.lastname: Tucker
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Allen
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
authors.forename: Rafal
authors.initials: R
authors.lastname: Luchowski
authors.forename: Marek
authors.initials: M
authors.lastname: Fol
authors.forename: Moshiur
authors.initials: M
authors.lastname: Rahman
authors.forename: Zygmunt
authors.initials: Z
authors.lastname: Gryczynski
authors.forename: Ignacy
authors.initials: I
authors.lastname: Gryczynski
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kurdowska
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D015153:Blotting, Western; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D018613:Microscopy, Confocal; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism*; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020239:Receptor Cross-Talk; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: C080568:Fc gamma receptor IIA; D017452:Receptors, IgG; D051197:Toll-Like Receptor 4; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human