Open AccessJournal Article
Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product.
Katsuaki Hoshino,Osamu Takeuchi,Taro Kawai,Hideki Sanjo,Tomohiko Ogawa,Yoshifumi Takeda,Kiyoshi Takeda,Shizuo Akira +7 more
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TLDR
It is demonstrated that TLR4 is the gene product that regulates LPS response, and a single point mutation of the amino acid that is highly conserved among the IL-1/Toll receptor family is found.Abstract:
The human homologue of Drosophila Toll (hToll), also called Toll-like receptor 4 (TLR4), is a recently cloned receptor of the IL-1/Toll receptor family. Interestingly, the TLR4 gene has been localized to the same region to which the Lps locus (endotoxin unresponsive gene locus) is mapped. To examine the role of TLR4 in LPS responsiveness, we have generated mice lacking TLR4. Macrophages and B cells from TLR4-deficient mice did not respond to LPS. All these manifestations were quite similar to those of LPS-hyporesponsive C3H/HeJ mice. Furthermore, C3H/HeJ mice have, in the cytoplasmic portion of TLR4, a single point mutation of the amino acid that is highly conserved among the IL-1/Toll receptor family. Overexpression of wild-type TLR4 but not the mutant TLR4 from C3H/HeJ mice activated NF-κB. Taken together, the present study demonstrates that TLR4 is the gene product that regulates LPS response.read more
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Differential expression and function of Toll-like receptors in Langerhans cells : comparison with splenic dendritic cells
Hiroshi Mitsui,Takahiro Watanabe,Hidehisa Saeki,Katsunori Mori,Hideki Fujita,Yayoi Tada,Akihiko Asahina,Koichiro Nakamura,Kunihiko Tamaki +8 more
TL;DR: Results may represent the functional heterogeneity between Langerhans cells and splenic dendritic cells, and are important for better understanding of innate immunity to bacterial infections differentially regulated in the skin and spleen.
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The role of Tyk2, Stat1 and Stat4 in LPS-induced endotoxin signals
Kenjirou Kamezaki,Kazuya Shimoda,Akihiko Numata,Tadashi Matsuda,Keiichi I. Nakayama,Mine Harada +5 more
TL;DR: Tyk2 is essential for LPS-induced endotoxin shock, and this signaling pathway is transduced by the activation of Stat1 and Stat4, which independently play substantial roles in the susceptibility to LPS.
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Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice
TL;DR: A critical role is suggested for the MyD88 pathway in initiating neuropathic pain, but a distinct role for the TRIF pathway and interferon in regulating neuropathicPain phenotypes in male mice is suggested.
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Role of Toll-like receptor responses for sepsis pathogenesis.
TL;DR: Using a model of severe polymicrobial septic peritonitis, it is shown that single TLRs are dispensable for the induction of innate immune responses under those conditions but genetic ablation of MyD88 or TRIF/type-I interferon signaling pathways prevented hyper- inflammation and attenuated the pathogenic consequences of sepsis indicating that dampening common signaling pathways may create a moderate signal strength which is associated with favorable immune responses.
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Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent Toll-like receptor 4 internalization and LPS-induced TBK1–IKKϵ–IRF3 axis activation
Hiroki Tsukamoto,Shino Takeuchi,Kanae Kubota,Yohei Kobayashi,Sao Kozakai,Ippo Ukai,Ayumi Shichiku,Misaki Okubo,Muneo Numasaki,Yoshitomi Kanemitsu,Yotaro Matsumoto,Tomonori Nochi,Kouichi Watanabe,Hisashi Aso,Yoshihisa Tomioka +14 more
TL;DR: It is shown that LBP-mediated LPS transfer to mCD14 is required for serum-dependent TLR4 internalization and activation of the TRIF pathway, which induces TLR adaptor molecule 1 (TRIF)-dependentactivation of the TBK1–IKKϵ–IRF3–IFN-β pathway.
References
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Journal ArticleDOI
Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene
Alexander Poltorak,Xiaolong He,Irina Smirnova,Mu Ya Liu,Christophe Van Huffel,Xin Du,Dale Birdwell,E. Alejos,M. Silva,Chris Galanos,Marina Freudenberg,Paola Ricciardi-Castagnoli,Betsy Layton,Bruce Beutler +13 more
TL;DR: The mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane.
Journal Article
Defective LPS signaling in C3 H/HeJ and C57 BL/10 ScCr mice: Mutations in Tlr4 Gene
Alexander Poltorak,Xiaolong He,Irina Smirnova,Mu Ya Liu,C. Van Huffel,Xin Du,Dale Birdwell,E. Alejos,M. Suva,Chris Galanos,Marina Freudenberg,Paola Ricciardi-Castagnoli,B. Layton,Bruce Beutler +13 more
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A human homologue of the Drosophila Toll protein signals activation of adaptive immunity
TL;DR: The cloning and characterization of a human homologue of the Drosophila toll protein (Toll) is reported, which has been shown to induce the innate immune response in adult Dosophila.
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The Dorsoventral Regulatory Gene Cassette spätzle/Toll/cactus Controls the Potent Antifungal Response in Drosophila Adults
TL;DR: It is shown that mutations in the Toll signaling pathway dramatically reduce survival after fungal infection and the intracellular components of the dorsoventral signaling pathway and the extracellular Toll ligand, spätzle, control expression of the antifungal peptide gene drosomycin in adults.
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Innate Immunity: The Virtues of a Nonclonal System of Recognition
TL;DR: Characterization of the nonclonal receptors of the innate immune system responsible for the adjuvant activity, and, evidently, for the associated side effects, would provide a powerful alternative approach, which would ultimately allow one to target these receptors directly.