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Cross-Talk between TLR4 and FcγReceptorIII (CD16) pathways


Rittirsch, D; Flierl, M A; Day, D E; Nadeau, B A; Zetoune, F S; Sarma, J V; Werner, C M; Wanner, G A; Simmen, H P; Huber-Lang, M S; Ward, P A (2009). Cross-Talk between TLR4 and FcγReceptorIII (CD16) pathways. PLoS Pathogens, 5(6):e1000464.

Abstract

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 FcgammaR 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 FcgammaRIII (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 FcRgamma-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 FcgammaRIII pathways are structurally and functionally connected at the receptor level and that TLR4 is indispensable for FcgammaRIII signaling via FcRgamma-subunit activation.

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 FcgammaR 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 FcgammaRIII (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 FcRgamma-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 FcgammaRIII pathways are structurally and functionally connected at the receptor level and that TLR4 is indispensable for FcgammaRIII signaling via FcRgamma-subunit activation.

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Other titles:Cross-talk between TLR4 and FcgammaReceptorIII (CD16) pathways
Contributors:Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America, Department of Traumatology, University Hospital Zurich, Zurich, Switzerland, Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, University Hospital Ulm, Ulm, Germany
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Trauma Surgery
04 Faculty of Medicine > University Hospital Zurich > Division of Surgical Research
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:June 2009
Deposited On:05 Feb 2010 09:30
Last Modified:09 Aug 2016 08:43
Publisher:Public Library of Science (PLoS)
ISSN:1553-7366
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1371/journal.ppat.1000464
PubMed ID:19503602
Permanent URL: http://doi.org/10.5167/uzh-29098

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