Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. - eScholarship
01 Jun 2005-Vol. 6, Iss: 6, pp 579-586
TL;DR: 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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Dissertation•
01 Jan 2003
135 citations
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.
Abstract: TYROBP (also known as DAP12 or KARAP) is a transmembrane adaptor protein initially described as a receptor-activating subunit component of natural killer (NK) cells. TYROBP is expressed in numerous cell types, including peripheral blood monocytes, macrophages, dendritic cells, and osteoclasts, but a key point of recent interest is related to the critical role played by TYROBP in the function of many receptors expressed on the plasma membrane of microglia. TYROBP is the downstream adaptor and putative signaling partner for several receptors implicated in Alzheimer's disease (AD), including SIRP1β, CD33, CR3, and TREM2. TYROBP has received much of its current notoriety because of its importance in brain homeostasis by signal transduction across those receptors. In this review, we provide an overview of evidence indicating that the biology of TYROBP extends beyond its interaction with these four ligand-binding ectodomain-intramembranous domain molecules. In addition to reviewing the structure and localization of TYROBP, we discuss our recent progress using mouse models of either cerebral amyloidosis or tauopathy that were engineered to be TYROBP-deficient or TYROBP-overexpressing. Remarkably, constitutively TYROBP-deficient mice provided a model of genetic resilience to either of the defining proteinopathies of AD. Learning behavior and synaptic electrophysiological function were preserved at normal physiological levels even in the face of robust cerebral amyloidosis (in APP/PSEN1;Tyrobp-/- mice) or tauopathy (in MAPTP301S;Tyrobp-/- mice). A fundamental underpinning of the functional synaptic dysfunction associated with each proteotype was an accumulation of complement C1q. TYROBP deficiency prevented C1q accumulation associated with either proteinopathy. Based on these data, we speculate that TYROBP plays a key role in the microglial sensome and the emergence of the disease-associated microglia (DAM) phenotype. TYROBP may also play a key role in the loss of markers of synaptic integrity (e.g., synaptophysin-like immunoreactivity) that has long been held to be the feature of human AD molecular neuropathology that most closely correlates with concurrent clinical cognitive function.
18 citations
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 .
Abstract: Triggering receptors expressed on myeloid cells (TREMs) encompass a family of cell-surface receptors chiefly expressed by granulocytes, monocytes and tissue macrophages. These receptors have been implicated in inflammation, neurodegenerative diseases, bone remodelling, metabolic syndrome, atherosclerosis and cancer. Here, I review the structure, ligands, signalling modes and functions of TREMs in humans and mice and discuss the challenges that remain in understanding TREM biology. In this Review, Marco Colonna provides a comprehensive summary of the triggering receptor expressed on myeloid cells (TREM) family of receptors. TREMs are important for modulating signalling in myeloid cells and have now been implicated in many different disease settings, including inflammatory diseases, autoimmunity, neurodegeneration and cancer.
10 citations
Dissertation•
29 Nov 2013
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.
Abstract: L’invasion de l’hote par un pathogene induit l’activation sequentielle des reponses immunitaires innees et adaptatives. La reconnaissance du pathogene par des recepteurs tels que les recepteurs de type Toll (TLRs) initie la reponse innee qui repose sur l’activation des lignees myeloides, la production de cytokines, de chemokines et de mediateurs pro-inflammatoires qui contribuent a l’eradication du pathogene. L’amplification incontrolee de la reaction inflammatoire est deletere pour l’organisme. Afin de mieux comprendre les mecanismes de regulation des reponses dependant de TLR2, recepteur implique dans la reconnaissance de bacteries, parasites ou champignons, nous avons etudie la composition des complexes multimoleculaires d’activation au sein des radeaux lipidiques. En utilisant des approches proteomiques complementaires, nous avons mis en evidence le role de la Src kinase Lyn et de la deshydrogenase IMPDHII apres engagement des heterodimeres TLR2/TLR1 ou TLR2/TLR6. La tyrosine kinase Lyn est indispensable a l’activation de NF-kB apres engagement de TLR2 et agit en phosphorylant la sous-unite p110 de la PI3-kinase (PI3-K). IMPDHII, cible de l’acide mycophenolique, est un regulateur negatif de la voie TLR2-NF-kB. IMPDHII interagit avec SHP1 pour inhiber la phosphorylation sur tyrosine de p85α, la sous-unite regulatrice de PI3-K, et prevenir la transactivation de NF-kB. Enfin, nous avons etudie le role d’un polymorphisme de IMPDHII dans la gravite du choc septique. Ces travaux affinent la comprehension de la regulation de la reponse dependant de TLR2 et permettent d’identifier de nouvelles cibles therapeutiques pour la prise en charge des infections graves.
10 citations
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.
Abstract: Innate immunity must be tightly controlled to eliminate invading pathogens while avoiding autoimmune or inflammatory diseases. Syk is essential for STAT1 activation at the early stage of IAV infection, which is critical for initial antiviral responses. ABSTRACT Spleen tyrosine kinase (Syk) has recently come forth as a critical regulator of innate immune response. Previous studies identify Syk as a key kinase for STAT1 activation at the early stage of influenza A virus (IAV) infection that is involved in initial antiviral immunity. However, the involvement of Syk in host antiviral immunity during the late phase of IAV infection and its effect on pathogenesis of the virus remain unknown. Here, we found through time course studies that Syk restrained antiviral immune response at the late stage of IAV infection, thereby promoting viral replication. Depletion of Syk suppressed IAV replication in vitro, whereas ectopic expression of Syk facilitated viral replication. Moreover, Syk-deficient mice were employed, and we observed that knockout of Syk rendered mice more resistant to IAV infection, as evidenced by a lower degree of lung injury, slower body weight loss, and an increased survival rate of Syk knockout mice challenged with IAV. Furthermore, we revealed that Syk repressed the interferon response at the late stage of viral infection. Loss of Syk potentiated the expression of type I and III interferons in both Syk-depleted cells and mice. Mechanistically, Syk interacted with TBK1 and modulated its phosphorylation status, thereby impeding TBK1 activation and restraining innate immune signaling that governs interferon response. Together, these findings unveil a role of Syk in temporally regulating host antiviral immunity and advance our understanding of complicated mechanisms underlying regulation of innate immunity against viral invasion. IMPORTANCE Innate immunity must be tightly controlled to eliminate invading pathogens while avoiding autoimmune or inflammatory diseases. Syk is essential for STAT1 activation at the early stage of IAV infection, which is critical for initial antiviral responses. Surprisingly, here a time course study showed that Syk suppressed innate immunity during late phases of IAV infection and thereby promoted IAV replication. Syk deficiency enhanced the expression of type I and III interferons, inhibited IAV replication, and rendered mice more resistant to IAV infection. Syk impaired innate immune signaling through impeding TBK1 activation. These data reveal that Syk participates in the initiation of antiviral defense against IAV infection and simultaneously contributes to the restriction of innate immunity at the late stage of viral infection, suggesting that Syk serves a dual function in regulating antiviral responses. This finding provides new insights into complicated mechanisms underlying interaction between virus and host immune system.
5 citations
References
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TL;DR: Rapid progress that has recently improved the understanding of the molecular mechanisms that mediate TLR signalling is reviewed.
Abstract: One of the mechanisms by which the innate immune system senses the invasion of pathogenic microorganisms is through the Toll-like receptors (TLRs), which recognize specific molecular patterns that are present in microbial components. Stimulation of different TLRs induces distinct patterns of gene expression, which not only leads to the activation of innate immunity but also instructs the development of antigen-specific acquired immunity. Here, we review the rapid progress that has recently improved our understanding of the molecular mechanisms that mediate TLR signalling.
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TL;DR: This method allows by simple means the generation of high numbers of murine DC with very low B cell or granulocyte contaminations, which will be valuable to study DC biology notably at the molecular level.
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TL;DR: The current state of the field regarding the natural ligands and molecular factors required for positive and negative selection are summarized and a model for how these disparate outcomes can be signaled via the same receptor is discussed.
Abstract: A functional immune system requires the selection of T lymphocytes expressing receptors that are major histocompatibility complex restricted but tolerant to self-antigens. This selection occurs predominantly in the thymus, where lymphocyte precursors first assemble a surface receptor. In this review we summarize the current state of the field regarding the natural ligands and molecular factors required for positive and negative selection and discuss a model for how these disparate outcomes can be signaled via the same receptor. We also discuss emerging data on the selection of regulatory T cells. Such cells require a high-affinity interaction with self-antigens, yet differentiate into regulatory cells instead of being eliminated.
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TL;DR: IRAK-M regulates TLR signaling and innate immune homeostasis and prevents dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAk-TRAF6 complexes.
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TL;DR: A physiological role for TNF alpha in regulating the development and organization of splenic follicular architecture and in the maturation of the humoral immune response is established.
Abstract: To investigate the role of TNF alpha in the development of in vivo immune response we have generated TNF alpha-deficient mice by gene targeting. Homozygous mutant mice are viable and fertile, develop lymph nodes and Peyer's patches and show no apparent phenotypic abnormalities, indicating that TNF alpha is not required for normal mouse development. In the absence of TNF alpha mice readily succumb to L. monocytogenes infections and show reduced contact hypersensitivity responses. Furthermore, TNF alpha knockout mice are resistant to the systemic toxicity of LPS upon D-galactosamine sensitization, yet they remain sensitive to high doses of LPS alone. Most interestingly, TNF alpha knockout mice completely lack splenic primary B cell follicles and cannot form organized follicular dendritic cell (FDC) networks and germinal centers. However, despite the absence of B cell follicles, Ig class-switching can still occur, yet deregulated humoral immune responses against either thymus-dependent (TD) or thymus-independent (TI) antigens are observed. Complementation of TNF alpha functioning by the expression of either human or murine TNF alpha transgenes is sufficient to reconstitute these defects, establishing a physiological role for TNF alpha in regulating the development and organization of splenic follicular architecture and in the maturation of the humoral immune response.
1,183 citations