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

ABSTRACT: 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 IL1?, TNF, and IL8 secretion. The silencing of MyD88 similarly led to the downregulation of TLR2, IL1?, 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.

SUBMITTER: Teixeira HS

PROVIDER: S-EPMC7464415 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Teixeira Hellen S HS Zhao Jiawei J Kazmierski Ethan E Kinane Denis F DF Benakanakere Manjunatha R MR

Cells 20200817 8

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 sti ...[more]

PMID: 32824595

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Project description:MyD88 is an adaptor protein in Toll-like receptor and interleukin 1 receptor mediated signaling pathways that plays an essential role in activation of immune responses following pathogen recognition. We investigate that role in the zebrafish embryo model by using a zebrafish mutant line that contains a premature stop condon in the gene encoding MyD88, leading to a truncated protein that lacks domains important for its normal function. We infected these MyD88 mutants and wildtype individuals with Salmonella typhimurium and Edwardsiella tarda to compare the resulting immune response by transcriptome profiling on total RNA isolated from single embryos. The data derived from these microarray experiments confirms the vital role of MyD88 in pathogen recognition and provides many leads for further research. This microarray study was designed to determine the effect of a truncation of the MyD88 protein on the innate immune response of zebrafish embryos during infection with Salmonella typhimurium and Edwardsiella tarda. Embryos used in this study are derived from an incross between parents heterozygous for the mutation. Both homozygous mutants and their wildtype siblings were selected by genotyping after being injected with the bacteria or PBS as control. RNA was isolated from single embryos and each treatment group consisted of three embryos: (1) Homozygous mutants injected with PBS 8 hours post infection (hpi), (2) wildtype siblings injected with PBS 8hpi, (3) S. typhimurium-infected homozygous mutants 8hpi, (4) S. typhimurium-infected wildtype siblings 8hpi, (5) Homozygous mutants injected with PBS 8 hours post infection (hpi) (E.tarda control), (6) wildtype siblings injected with PBS 8hpi (E. tarda control), (7) E. tarda-infected homozygous mutants 8hpi, (8) E. tarda-infected wildtype siblings 8hpi. Embryos were grown at 28.5M-bM-^@M-^S30M-BM-0C in egg water and manually dechorionated at 24 hours post fertilization (hpf). Subsequently, embryos were infected at 28 hpf by micro-injecting 200 colony forming units (CFU) of S. typhimurium SL1027 or E. Tarda FL-F60, or were mock-injected with buffer as a control. After injections embryos were transferred into fresh egg water and incubated for 8 h or 4 days at 28M-BM-0C. After the incubation period, single embryos were snap-frozen in liquid nitrogen and RNA was isolated for microarray analysis. All treatment groups were analyzed using a common reference approach.

Dataset Information

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

Publications

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

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