Bruton's Tyrosine Kinase Mediates FcγRIIa / TLR4 Receptor Cross-Talk in Human Neutrophils.

Krupa A, Fudala R, Florence JM, Tucker T, Allen TC, Standiford TJ, Luchowski R, Fol M, Rahman M, Gryczynski Z, Gryczynski I, Kurdowska AK.

Source

Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas, United States.

Abstract

Previous observations made 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) is an important prognostic indicator of the development and ultimate outcome of ALI/ARDS. We also showed that these complexes display pro-inflammatory activity towards neutrophils through engagement of FcγRIIa receptors. Because sepsis is one of the most common risk factors for ALI/ARDS, the initial goal of our current study was to investigate effect of lipopolysaccharide (LPS) on expression of FcγRIIa receptors in neutrophils. Our results indicate that LPS triggers an increase in expression of FcγRIIa on the neutrophil surface, and this leads to shortening of the molecular distance between FcγRIIa and 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 existence of Btk dependent molecular cooperation between FcγRIIa and TLR4 signaling cascades in LPS "primed" human neutrophils. Furthermore, we have used FRET (Fluorescence Lifetime Imaging) to study the interaction 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.

TimAllenMDJD

Monday, December 17, 2012