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

Agnieszka Krupa, Rafal Fudala, Jon M. Florence, Torry Tucker, Timothy C. Allen, Theodore J. Standiford, Rafal Luchowski, Marek Fol, Moshiur Rahman, Zygmunt Gryczynski, Ignacy Gryczynski, Anna K. Kurdowska

Research output: Contribution to journalArticle

17 Scopus citations

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 out come 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.

Original languageEnglish (US)
Pages (from-to)240-249
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume48
Issue number2
DOIs
StatePublished - Feb 1 2013

Keywords

  • Btk
  • FcγRIIa
  • Neutrophil
  • TLR4

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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    Krupa, A., Fudala, R., Florence, J. M., Tucker, T., Allen, T. C., Standiford, T. J., Luchowski, R., Fol, M., Rahman, M., Gryczynski, Z., Gryczynski, I., & Kurdowska, A. K. (2013). Bruton's tyrosine kinase mediates FcγRIIa/Toll-like receptor-4 receptor crosstalk in human neutrophils. American journal of respiratory cell and molecular biology, 48(2), 240-249. https://doi.org/10.1165/rcmb.2012-0039OC