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

1
Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19004, USA
2
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19004, USA
3
Periodontology Department, Bern Dental School, University of Bern, 3012 Bern, Switzerland
*
Author to whom correspondence should be addressed.
Present address: Department of Pathology, Wayne State University School of Medicine, 541 East Canfield Ave., Scott Hall 9215, Detroit, MI 48201, USA.
Cells 2020, 9(8), 1910; https://doi.org/10.3390/cells9081910
Received: 30 June 2020 / Revised: 12 August 2020 / Accepted: 12 August 2020 / Published: 17 August 2020
(This article belongs to the Section Cell Signaling)
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. View Full-Text
Keywords: human gingival epithelial cells; TLR3; MyD88; HMGB1; Hsp60; pro-inflammatory cytokine human gingival epithelial cells; TLR3; MyD88; HMGB1; Hsp60; pro-inflammatory cytokine
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MDPI and ACS Style

Teixeira, H.S.; Zhao, J.; Kazmierski, E.; Kinane, D.F.; Benakanakere, M.R. TLR3-Dependent Activation of TLR2 Endogenous Ligands via the MyD88 Signaling Pathway Augments the Innate Immune Response. Cells 2020, 9, 1910. https://doi.org/10.3390/cells9081910

AMA Style

Teixeira HS, Zhao J, Kazmierski E, Kinane DF, Benakanakere MR. TLR3-Dependent Activation of TLR2 Endogenous Ligands via the MyD88 Signaling Pathway Augments the Innate Immune Response. Cells. 2020; 9(8):1910. https://doi.org/10.3390/cells9081910

Chicago/Turabian Style

Teixeira, Hellen S., Jiawei Zhao, Ethan Kazmierski, Denis F. Kinane, and Manjunatha R. Benakanakere. 2020. "TLR3-Dependent Activation of TLR2 Endogenous Ligands via the MyD88 Signaling Pathway Augments the Innate Immune Response" Cells 9, no. 8: 1910. https://doi.org/10.3390/cells9081910

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