Absence of MyD88 results in enhanced TLR3-dependent phosphorylation of IRF3 and increased IFN-(beta) and RANTES production

Siednienko, Jakub; Gajanayake, Thusitha; Fitzgerald, Katherine A; Moynagh, Paul; Miggin, Sinéad M (2011). Absence of MyD88 results in enhanced TLR3-dependent phosphorylation of IRF3 and increased IFN-(beta) and RANTES production. Journal of immunology, 186(4), pp. 2514-22. Bethesda, Md.: American Association of Immunologists 10.4049/jimmunol.1003093

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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- . 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- 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- induction, MyD88 negatively regulates TLR3-, but not TLR4-, mediated IFN- and RANTES production; this process is mechanistically distinct from that employed by Mal/TIRAP. We show that MyD88 inhibits IKK -, but not TBK1-, induced activation of IRF3. In doing so, MyD88 curtails TLR3 ligand-induced IFN- 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- . Our study offers a new role for MyD88 in restricting TLR3 signaling through a hitherto unknown mechanism whereby MyD88 specifically impairs IKK -mediated induction of IRF3 and concomitant IFN- and RANTES production.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Orthopaedic, Plastic and Hand Surgery (DOPH) > Clinic of Plastic and Hand Surgery > Plastic, Reconstructive and Aesthetic Surgery

UniBE Contributor:

Gajanayake, Thusitha

ISSN:

0022-1767

Publisher:

American Association of Immunologists

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:10

Last Modified:

04 May 2014 23:05

Publisher DOI:

10.4049/jimmunol.1003093

PubMed ID:

21248248

Web of Science ID:

000286882700071

URI:

https://boris.unibe.ch/id/eprint/1288 (FactScience: 202644)

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