TLR3-Dependent Activation of TLR2 Endogenous Ligands via the MyD88 Signaling Pathway Augments the Innate Immune Response.

Teixeira, Hellen S; Zhao, Jiawei; Kazmierski, Ethan; Kinane, Denis F; Benakanakere, Manjunatha R (2020). TLR3-Dependent Activation of TLR2 Endogenous Ligands via the MyD88 Signaling Pathway Augments the Innate Immune Response. Cells, 9(8) MDPI 10.3390/cells9081910

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The role of the adaptor molecule MyD88 is thought to be independent of Toll-like receptor 3 (TLR3) signaling. In this report, we demonstrate a previously unknown role of MyD88 in TLR3 signaling in inducing endogenous ligands of TLR2 to elicit innate immune responses. Of the various TLR ligands examined, the TLR3-specific ligand polyinosinic:polycytidylic acid (poly I:C), significantly induced TNF production and the upregulation of other TLR transcripts, in particular, TLR2. Accordingly, TLR3 stimulation also led to a significant upregulation of endogenous TLR2 ligands mainly, HMGB1 and Hsp60. By contrast, the silencing of TLR3 significantly downregulated MyD88 and TLR2 gene expression and pro-inflammatory IL1β, TNF, and IL8 secretion. The silencing of MyD88 similarly led to the downregulation of TLR2, IL1β, TNF and IL8, thus suggesting MyD88 to somehow act downstream of TLR3. Corroborating in vitro data, Myd88-/- knockout mice downregulated TNF, CXCL1; and phospho-p65 and phospho-IRF3 nuclear localization, upon poly I:C treatment in a mouse model of skin infection. Taken together, we identified a previously unknown role for MyD88 in the TLR3 signaling pathway, underlying the importance of TLRs and adapter protein interplay in modulating endogenous TLR ligands culminating in pro-inflammatory cytokine regulation.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > School of Dental Medicine > Department of Periodontology
04 Faculty of Medicine > School of Dental Medicine > School of Dental Medicine, Periodontics Research

ISSN:

2073-4409

Publisher:

MDPI

Language:

English

Submitter:

Doris Burri

Date Deposited:

16 Feb 2021 17:24

Last Modified:

16 Feb 2021 17:24

Publisher DOI:

10.3390/cells9081910

PubMed ID:

32824595

Uncontrolled Keywords:

HMGB1 Hsp60 MyD88 TLR3 human gingival epithelial cells pro-inflammatory cytokine

BORIS DOI:

10.48350/152209

URI:

https://boris.unibe.ch/id/eprint/152209

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