Open AccessCross-Talk between TLR4 and FcγReceptorIII (CD16) Pathways
Author(s) -
Daniel Rittirsch,
Michael A. Flierl,
Danielle E. Day,
Brian A. Nadeau,
Firas S. Zetoune,
J. Vidya Sarma,
Clément M. L. Werner,
Guido A. Wanner,
Hans Peter Simmen,
Markus HuberLang,
Peter A. Ward
Publication year - 2009
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1000464
Subject(s) - tlr4 , immunoreceptor tyrosine based activation motif , receptor , fc receptor , microbiology and biotechnology , cd16 , pattern recognition receptor , lipopolysaccharide , in vitro , toll like receptor , immune system , biology , immunology , signal transduction , chemistry , innate immune system , tyrosine kinase , biochemistry , syk , cd8 , cd3
Pathogen-pattern-recognition by Toll-like receptors (TLRs) and pathogen clearance after immune complex formation via engagement with Fc receptors (FcRs) represent central mechanisms that trigger the immune and inflammatory responses. In the present study, a linkage between TLR4 and FcγR was evaluated in vitro and in vivo . Most strikingly, in vitro activation of phagocytes by IgG immune complexes (IgGIC) resulted in an association of TLR4 with FcγRIII (CD16) based on co-immunoprecipitation analyses. Neutrophils and macrophages from TLR4 mutant (mut) mice were unresponsive to either lipopolysaccharide (LPS) or IgGIC in vitro , as determined by cytokine production. This phenomenon was accompanied by the inability to phosphorylate tyrosine residues within immunoreceptor tyrosine-based activation motifs (ITAMs) of the FcRγ-subunit. To transfer these findings in vivo , two different models of acute lung injury (ALI) induced by intratracheal administration of either LPS or IgGIC were employed. As expected, LPS-induced ALI was abolished in TLR4 mut and TLR4 −/− mice. Unexpectedly, TLR4 mut and TLR4 −/− mice were also resistant to development of ALI following IgGIC deposition in the lungs. In conclusion, our findings suggest that TLR4 and FcγRIII pathways are structurally and functionally connected at the receptor level and that TLR4 is indispensable for FcγRIII signaling via FcRγ-subunit activation.