Absence of MyD88 results in enhanced TLR3-dependent phosphorylation of IRF3 and increased IFN-β and RANTES production.
Toll-like receptors are a group of pattern-recognition receptors that play a crucial role in "danger" recognition and induction of the innate immune response against bacterial and viral infections. TLR3 has emerged as a key sensor of viral dsRNA, resulting in the induction of the anti-viral molecule, IFN-β. Thus, a clearer understanding of the biological processes that modulate TLR3 signaling is essential. Previous studies have shown that the TLR adaptor, Mal/TIRAP, an activator of TLR4, inhibits TLR3-mediated IFN-β induction through a mechanism involving IRF7. In this study, we sought to investigate whether the TLR adaptor, MyD88, an activator of all TLRs except TLR3, has the ability to modulate TLR3 signaling. Although MyD88 does not significantly affect TLR3 ligand-induced TNF-α induction, MyD88 negatively regulates TLR3-, but not TLR4-, mediated IFN-β and RANTES production; this process is mechanistically distinct from that employed by Mal/TIRAP. We show that MyD88 inhibits IKKε-, but not TBK1-, induced activation of IRF3. In doing so, MyD88 curtails TLR3 ligand-induced IFN-β induction. The present study shows that while MyD88 activates all TLRs except TLR3, MyD88 also functions as a negative regulator of TLR3. Thus, MyD88 is essential in restricting TLR3 signaling, thereby protecting the host from unwanted immunopathologies associated with the excessive production of IFN-β. Our study offers a new role for MyD88 in restricting TLR3 signaling through a hitherto unknown mechanism whereby MyD88 specifically impairs IKKε-mediated induction of IRF3 and concomitant IFN-β and RANTES production.
Department of Biology, Institute of Immunology, National University of Ireland Maynooth, Maynooth, County Kildare, Ireland.
Jakub
J
Siednienko
Thusitha
T
Gajanayake
Katherine A
KA
Fitzgerald
Paul
P
Moynagh
Sinéad M
SM
Miggin
D000818:Animals; D002460:Cell Line; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015536:Down-Regulation / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000502:physiology; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D015398:Signal Transduction / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology*
C483024:CCL5 protein, human; D018946:Chemokine CCL5; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D051550:I-kappa B Kinase