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Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. - eScholarship

Jessica A. Hamerman, +3 more
- Vol. 6, Iss: 6, pp 579-586
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TLDR
This article examined the responses of mice lacking DAP12 to stimulation through Toll-like receptors (TLRs) and found that one or more DAP-pairing receptors negatively regulate signaling through TLRs.
Abstract
DAP12 is a signaling adaptor containing an immunoreceptor tyrosine-based activation motif (ITAM) that pairs with receptors on myeloid cells and natural killer cells. We examine here the responses of mice lacking DAP12 to stimulation through Toll-like receptors (TLRs). Unexpectedly, DAP12-deficient macrophages produced higher concentrations of inflammatory cytokines in response to a variety of pathogenic stimuli. Additionally, macrophages deficient in spleen tyrosine kinase (Syk), which signals downstream of DAP12, showed a phenotype identical to that of DAP12-deficient macrophages. DAP12-deficient mice were more susceptible to endotoxic shock and had enhanced resistance to infection by the intracellular bacterium Listeria monocytogenes. These data suggest that one or more DAP12-pairing receptors negatively regulate signaling through TLRs.

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Citations
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Microglial TYROBP/DAP12 in Alzheimer’s disease: Transduction of physiological and pathological signals across TREM2

TL;DR: In this article , the authors provide an overview of evidence indicating that the biology of the TYROBP extends beyond its interaction with these four ligand-binding ectodomain-intramembranous domain molecules.
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The biology of TREM receptors

TL;DR: The triggering receptor expressed on myeloid cells (TREM) family of receptors have been investigated in many different disease settings, including inflammatory diseases, autoimmunity, neurodegeneration and cancer as mentioned in this paper .
Dissertation

Nouveaux régulateurs de la signalisation TLR2-NF-kB

TL;DR: In this paper, le role of TLR2-NF-kB in lignees myeloides reaction is investigated, and the composition of complexes multimoleculaires d'activation au sein des radeaux lipidiques.
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Syk Facilitates Influenza A Virus Replication by Restraining Innate Immunity at the Late Stage of Viral Infection

TL;DR: Surprisingly, a time course study showed that Syk suppressed innate immunity during late phases of IAV infection and thereby promoted IAV replication, providing new insights into complicated mechanisms underlying interaction between virus and host immune system.
References
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Journal ArticleDOI

Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts.

TL;DR: The molecular defect inPLOSL is characterized by identifying one large deletion in all Finnish PLOSL alleles and another mutation in a Japanese patient, both representing loss-of-function mutations in the gene encoding TYRO protein tyrosine kinase binding protein (TYROBP).
Journal ArticleDOI

Natural killer cells as an initial defense against pathogens.

TL;DR: The mechanisms by which NK cells recognize and respond to viruses, parasites and bacteria, and on the unique role of NK cells in innate immunity to infection are focused on.
Journal ArticleDOI

Syk is required for integrin signaling in neutrophils.

TL;DR: It is shown that Syk is also an essential component of integrin signaling in neutrophils, and defects in integrin-mediated activation did not impair the Integrin-dependent in vitro or in vivo migration of syk(-/-) neutrophil or of cells deficient in Src-family kinases.
Journal ArticleDOI

Characterization of the CD200 receptor family in mice and humans and their interactions with CD200.

TL;DR: The first characterization of human CD200R (hCD200R) is reported and its binding characteristics to hCD200 are defined, and two mCD200 receptor-like family members were shown to pair with the activatory adaptor protein, DAP12, suggesting that these receptors would transmit strong activating signals in contrast to the apparent inhibitory signal delivered by triggering the CD 200R.
Journal ArticleDOI

Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b

TL;DR: CD11b deficiency enhanced TLR-mediated responses in macrophages, rendering mice more susceptible to endotoxin shock and Escherichia coli–caused sepsis, and inhibits TLR signaling in innate immune responses.
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