Toll-like receptor signalling

Akira, Shizuo; Takeda, Kiyoshi

doi:10.1038/nri1391

Cited by 7,265 publications

(6,495 citation statements)

References 142 publications

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“…Through the expression of pattern-recognition receptors (PPRs) such as Toll-like receptors (TLRs), DCs are able to sense a wide array of pathogens and mount an appropriate T-helper (Th) cell response [4]. Naïve CD4 1 T-cell precursors can differentiate into a variety of Th-cell lineages characterized by the cytokines produced: Th1 cells secrete predominately IFN-g, Th2 cells release IL-4, IL-5, and IL-13 and Th17 cells typically produce IL-17 [5].…”

Section: Introductionmentioning

confidence: 99%

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Pletinckx

Stijlemans²,

Pavlović

et al. 2011

Eur J Immunol

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DCs represent the major cell type leading to polarized T-helper (Th) cell responses in vivo. Here, we asked whether the instruction of murine Th2 responses by DCs matured with the proinflammatory cytokine TNF is qualitatively different from maturation by different types of TLR4/MyD88-dependent variant-specific surface glycoproteins (VSGs) of Trypanosoma brucei (T. brucei). The results obtained by analyzing DC surface markers, Notch ligand mRNA, cytokines, asthma, and experimental autoimmune encephalomyelitis (EAE) models as well as performing microarrays indicate that both types of stimuli induce similar inflammatory, semi-mature DC profiles. DCs matured by TNF or VSG treatment expressed a common inflammatory signature of 24 genes correlating with their Th2-polarization capacity. However, the same 24 genes and 4498 additional genes were expressed by DCs treated with LPS that went on to induce Th1 cells. These findings support the concept of a default pathway for Th2-cell induction in DCs matured under suboptimal or inflammatory conditions, independent of the surface receptors and signaling pathways involved. Our data also indicate that quantitative differences in DC maturation might direct Th2-vs Th1-cell responses, since suboptimally matured inflammatory DCs induce default Th2-cell maturation, whereas fully mature DCs induce Th1-cell maturation.Key words: DCs . microarray . Th2 cells . TNF . Trypanosoma Supporting Information available online IntroductionDCs play a fundamental role in the induction of adaptive immune responses as well as in the maintenance of peripheral tolerance [1][2][3]. Through the expression of pattern-recognition receptors (PPRs) such as Toll-like receptors (TLRs), DCs are able to sense a wide array of pathogens and mount an appropriate T-helper (Th) cell response [4]. Naïve CD4 1 T-cell precursors can differentiate into a variety of Th-cell lineages characterized by the cytokines produced: Th1 cells secrete predominately IFN-g, Th2 cells release IL-4, IL-5, and IL-13 and Th17 cells typically produce . Although the contribution of DCs for CD4 1 Th-cell polarization is under debate [6], several DC-derived mechanisms have been described to significantly direct Th-cell phenotypes. 3479DCs change their maturation status by upregulating surface expression of MHC class II and costimulatory molecules and by producing a defined set of cytokines to optimally induce distinct Th-cell responses [7][8][9]. Due to their immunostimulatory function, DCs are of particular interest in immunotherapy settings, such as cancer therapy and infectious disease intervention [10,11]. Thus, the Th-cell polarizing profile defined by the maturation signature of DCs is of vital interest. Several membrane markers on DCs and soluble factors secreted by DCs have been described to polarize toward Th2 responses. These include costimulatory molecules such as OX40 [12], , the Notch family member Jagged-2 [14], the cytokine IL-6 [15], or arachidonic acid metabolites such as PGE 2 [16][17][18]. Much less is known about the fac...

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Section: Introductionmentioning

confidence: 99%

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Pletinckx

Stijlemans²,

Pavlović

et al. 2011

Eur J Immunol

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“…For TLR7 and 8, the required adaptor is the Myeloid differentiation primary response gene 88 (MyD88). TLR3 transmits signals via TIR domain-containing adaptor inducing IFN-β (TRIF) [31]. The adaptor proteins MyD88 and TRIF initiate a signaling cascade that consists of a complex network of signaling molecules.…”

Section: In Vitro Transcribed (Ivt) Mrnamentioning

confidence: 99%

“…Both pathways converge in the activation of the IκB kinase (IKK) complex and the IKK-related kinases TANK-binding kinase 1 (TBK1) and IKKε. The IKK complex, which includes the kinases IKKα and IKKβ as well as the regulatory subunit IKKγ/NEMO, is responsible for the activation of NF-κB, whereas TBK1 and IKKε phosphorylate and activate IRF3 and IRF7 [31,44,45]. In unstimulated cells, NF-κB, IRF3…”

Section: In Vitro Transcribed (Ivt) Mrnamentioning

confidence: 99%

Evading innate immunity in nonviral mRNA delivery: don’t shoot the messenger

Devoldere

Dewitte

Smedt

2016

Drug Discovery Today

108

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Teaser:This review presents an overview of the immune-related hurdles that limit mRNA advance for non-immunotherapy related applications and suggest some promising methods to reduce this 'unwanted' innate immune response. Author photographs and biographiesJoke Devoldere (1990) Her project lies on the interface between material science and immunology as it aims to develop novel micro-and nanomaterials for the delivery of antigen-coding mRNA to induce antitumor immunity. With her research, she won several awards, among which the "Therapeutic use of microbubbles" oral presentation award (Rotterdam, The Netherlands) and the Jan Feijen poster prize at the 13 th European symposium on controlled drug delivery (Egmond aan Zee, The Netherlands). Evading innate immunity in non-viral mRNA delivery: don't shoot the messenger AbstractIn de field of non-viral gene therapy, in vitro transcribed (IVT) mRNA has emerged as a promising tool for the delivery of genetic information. Over the past few years it has become widely known the introduction of IVT mRNA into mammalian cells elicits an innate immune response which has favored mRNA use towards immunotherapeutic vaccination strategies. However, for non-immunotherapy related applications this intrinsic immune-stimulatory activity directly interferes with the aimed therapeutic outcome, as it can seriously compromise the expression of the desired protein. This review presents an overview of the immune-related obstacles that limit mRNA advance for non-immunotherapy related applications.

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“…8 Located at the plasma membrane and in endosomes, TLRs bind to microbial pathogen-associated molecular patterns (PAMPs) as well as host-derived danger-associated molecular patterns (DAMPs). 9 Therefore, TLR/MyD88-signaling constitutes a major functional hub between the gut and the microbiome. TLRs as well as interleukin-1 family receptors recruit the intracellular adaptor proteins MyD88 and TRIF, respectively, and induce distinct signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Cell-type specific MyD88 signaling is required for intestinal tumor initiation and progression to malignancy

Holtorf

Conrad²,

Holzmann³

et al. 2018

OncoImmunology

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The signal adapter MyD88, an essential component of Toll-like receptor (TLR) signaling, is important for gut-microbiome interactions. However, its contribution to cancer and its cell-type specific functions are controversially discussed. Therefore, we generated new tissue-specific mouse models and analyzed the clinical importance in human colorectal cancer. A gene-trap was inserted into the murine Myd88 gene (Myd88LSL), yielding MyD88-deficient background with Cre-mediated re-expression in myeloid (MYEL) or intestinal epithelial cells (IECs). These lines were bred with the Apc1638N model that develops invasive adenocarcinoma and analyzed at 12 months. Further, two patient collectives of colorectal cancer (n = 61, and n = 633) were analyzed for expression of Myd88 and TLRs. MyD88 expression was significantly increased in carcinomas, and increased intratumoral levels of MyD88 and TLR pathway components were associated with significantly shorter disease-free (P = .011), and overall survival (P < .0001). In accordance, fully MyD88-deficient mice showed highly significantly decreased tumor incidence, tumor numbers, increased survival, and, importantly, fully lacked malignant lesions. Thus, MyD88 is essential for tumorigenesis and especially progression to malignancy. Tissue-specific re-expression of MyD88 highly significantly increased tumor initiation by differing mechanisms. In intestinal epithelia, MyD88 enhanced epithelial turnover, whereas in myeloid cells, it led to increased production of tumor- and stemness-enhancing cytokines, significantly associated with altered expression of adaptive immune genes. However, neither re-expression of MyD88 in IECs or myeloid cells was sufficient for malignant progression to carcinoma. Thus, MyD88 crucially contributes to colorectal cancer initiation and progression with non-redundant and cell-type specific functions, constituting an attractive therapeutic target.

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Toll-like receptor signalling

Cited by 7,265 publications

References 142 publications

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Evading innate immunity in nonviral mRNA delivery: don’t shoot the messenger

Cell-type specific MyD88 signaling is required for intestinal tumor initiation and progression to malignancy

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