Cross-Talk between TLR4 and FcγReceptorIII (CD16) Pathways

PLoS Pathogens

Firas S. Zetoune¹  Clement M. Werner¹  Daniel Rittirsch¹  Brian A. Nadeau¹  J. Vidya Sarma¹  Danielle E. Day¹  Peter A. Ward²  Markus S. Huber-Lang³  Hans-Peter Simmen³  Michael A. Flierl³  Guido A. Wanner³ 

[1] Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America;Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, University Hospital Ulm, Ulm, Germany;Department of Traumatology, University Hospital Zurich, Zurich, Switzerland

关键词: Macrophages;    Immune receptor signaling;    Toll-like receptors;    Immune complex;    Cytokines;    Phosphorylation;    Immune receptors;    Phagocytes;   

DOI  :  10.1371/journal.ppat.1000464

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY