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Am J Respir Cell Mol Biol. 2013 Feb;48(2):240-9. doi: 10.1165/rcmb.2012-0039OC. Epub 2012 Dec 13.

Bruton's tyrosine kinase mediates FcγRIIa/Toll-like receptor-4 receptor crosstalk in human neutrophils.

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  • 1Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA.


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.

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