Cross-Talk between TLR4 and FcγReceptorIII (CD16) Pathways

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 evaluate...

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Bibliographic Details
Published in:	PLoS pathogens Vol. 5; no. 6; p. e1000464
Main Authors:	Rittirsch, Daniel, Flier, Michael A, Day, Danielle E, Nadeau, Brian A, Zetoune, Firas S, Sarma, J. Vidya, Werner, Clement M, Wanner, Guido A, Simmen, Hans-Peter, Huber- Lang, Markus S, Ward, Peter A
Format:	Journal Article
Language:	English
Published:	San Francisco, USA Public Library of Science 01-06-2009
Subjects:	Fc receptors Immunoglobulin G Immunology/Cellular Microbiology and Pathogenesis Immunology/Immune Response Macrophages Pathology/Cellular Pathology Pathology/Immunology Physiological aspects United States Switzerland Germany
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Summary:	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.sup.-/-] mice. Unexpectedly, TLR4 mut and [TLR4.sup.-/-] 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.
Bibliography:	Conceived and designed the experiments: DR MAF JVS MSHL PAW. Performed the experiments: DR MAF DED BAN FSZ. Analyzed the data: DR MAF DED BAN FSZ JVS CMW GAW HPS MSHL PAW. Contributed reagents/materials/analysis tools: DR FSZ. Wrote the paper: DR PAW.
ISSN:	1553-7374 1553-7366 1553-7374
DOI:	10.1371/journal.ppat.1000464