Novel signaling interactions between proteinase-activated receptor 2 and Toll-like receptors in vitro and in vivo.
Toll-like receptors (TLRs) and proteinase-activated receptors (PARs) function as innate immune biosensors in mucosal epithelial cells (ECs). We previously reported the functional and physical interactions between TLR4 and PAR(2). We have extended these findings herein by showing the cooperation between PAR(2) and TLR2, TLR3, or TLR4 for activation of nuclear factor-kappaB-dependent signaling in mucosal EC lines. In contrast, activation of PAR(2) negatively regulated TLR3-dependent antiviral pathway, blunting the expression of TLR3/interferon regulatory factor-3 (IRF-3)-driven genes, as well as activation of IRF-3 and STAT1. Consistent with these in vitro observations, PAR(2)(-/-) and TLR4(-/-) mice, which were refractory to footpad edema induced by PAR(2) agonist peptide, were protected from mouse-adapted H1N1 influenza A virus-induced lethality when compared to wild-type (WT) mice. These data support and extend our recently described, novel model of PAR(2)-TLR4 "receptor cooperativity" and highlight the complexity of signaling integration between heterologous innate immune biosensors.
Department of Microbiology and Immunology, University of Maryland, Baltimore (UMB), School of Medicine, Baltimore, Maryland, USA.
Q M
QM
Nhu
K
K
Shirey
J R
JR
Teijaro
D L
DL
Farber
S
S
Netzel-Arnett
T M
TM
Antalis
A
A
Fasano
S N
SN
Vogel
D000818:Animals; D002460:Cell Line; D004487:Edema; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology* / Q000472:pathogenicity; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D044464:Receptor, PAR-2 / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism*
D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D016328:NF-kappa B; D044464:Receptor, PAR-2; D050794:STAT1 Transcription Factor; D051193:Toll-Like Receptors