Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

Kanno, Ariyo; Tanimura, Natsuko; Ishizaki, Masayuki; Ohko, Kentaro; Motoi, Yuji; Onji, Masahiro; Fukui, Ryutaro; Shimozato, Takaichi; Yamamoto, Kazuhide; Shibata, Takuma; Sano, Shigetoshi; Sugahara–Tobinai, Akiko; Takai, Toshiyuki; Ohto, Umeharu; Shimizu, Toshiyuki; Saitoh, Shu‐ichi; Miyake, Kensuke

doi:10.1038/ncomms7119

Cited by 70 publications

(71 citation statements)

References 31 publications

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“…Also, cell surface expression of mouse TLR7 has been shown in splenic DCs and bone-marrow derived macrophages. Anti-TLR7 antibody inhibits TLR7 responses in vitro and in vivo [44]. TLR3 and mouse TLR7 need to be processed in the endosome, so trafficking between endosomes and the plasma membrane should regulate the cell surface expression of mature TLR3 and mouse TLR7.…”

Section: Rna Sensing In the Endosomal Compartmentmentioning

confidence: 99%

Extracellular RNA Sensing by Pattern Recognition Receptors

et al. 2018

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RNA works as a genome and messenger in RNA viruses, and it sends messages in most of the creatures of the Earth, including viruses, bacteria, fungi, plants, and animals. The human innate immune system has evolved to detect single- and double-stranded RNA molecules from microbes by pattern recognition receptors and induce defense reactions against infections such as the production of type I interferons and inflammatory cytokines. To avoid cytokine toxicity causing chronic inflammation or autoimmunity by sensing self-RNA, the activation of RNA sensors is strictly regulated. All of the Toll-like receptors that recognize RNA are localized to endosomes/lysosomes, which require internalization of RNA for sensing through an endocytic pathway. RIG-I-like receptors sense RNA in cytosol. These receptors are expressed in a cell type-specific fashion, enabling sensing of RNA for a wide range of microbial invasions. At the same time, both endosomal and cytoplasmic receptors have strategies to respond only to RNA of pathogenic microorganisms or dying cells. RNA are potential vaccine adjuvants for immune enhancement against cancer and provide a benefit for vaccinations. Understanding the detailed molecular mechanisms of the RNA-sensing system will help us to broaden the clinical utility of RNA adjuvants for patients with incurable diseases.

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Section: Rna Sensing In the Endosomal Compartmentmentioning

confidence: 99%

Extracellular RNA Sensing by Pattern Recognition Receptors

et al. 2018

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“…to B6 mice on the day of immunization. At 13 d postimmunization, uveitogenic T cells were isolated and restimulated with IRBP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and APCs under nonpolarizing conditions in the presence of Ag. As shown in Fig.…”

Section: Cl097-stimulated Dcs Enhance Irbp-specific Th17 Responses Anmentioning

confidence: 99%

“…TLR7 was implicated in a variety of autoimmune disorders (12)(13)(14), and engagement of TLR7 endows human DCs with the ability to regulate the effector function of Th17 cells (15,16). Recently, targeting cell surface TLR7 in DCs was shown to be a promising strategy for treating autoimmune diseases (17). However, little is known about the mechanism by which TLR7 engagement regulates interphotoreceptor retinoid-binding protein (IRBP)-specific Th17 cells in EAU.…”

mentioning

confidence: 99%

TLR7 Engagement on Dendritic Cells Enhances Autoreactive Th17 Responses via Activation of ERK

Xiao

Sun

et al. 2016

The Journal of Immunology

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In this study, we showed that TLR7 activation significantly promoted interphotoreceptor retinoid-binding protein (IRBP)-specific Th17 responses by upregulating RORγt, IL-17, GM-CSF, and IL-23R expression in experimental autoimmune uveitis mice. In vivo administration of CL097 activated dendritic cells (DCs) and endowed them with an increased ability to activate IRBP-specific Th17 cells. CL097-treated DCs (CL097-DCs) formed a cytokine milieu that favored the generation and maintenance of Th17 cells by stimulating IL-1β, IL-6, and IL-23 expression. Furthermore, IRBP-specific T cells from immunized mice injected with CL097-DCs produced more IL-17 and transferred more severe experimental autoimmune uveitis than did those from mice injected with DCs. The enhanced immunostimulatory activities of CL097-DCs depended on JNK, ERK, and p38 activation. Blockade of ERK, but not p38 or JNK, completely abolished the Th17 responses induced by CL097-DCs. Collectively, our findings suggest that CL097 treatment significantly promotes autoreactive IL-17+ T cell responses through enhancing DC activation, which is mediated, at least in part, via the activation of ERK signaling.

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“…1). TLR7 has also recently been described on the cell surface of B cells [18], and it is likely that axons express TLR7 on the cell surface as well. Stimulation of neuronal TLR7 triggers a MyD88-independent pathway and subsequent activation of nociceptors [19].…”

Section: Tlr7 Expression Signaling and Ligandsmentioning

confidence: 99%

Toll-Like Receptor 7-Targeted Therapy in Respiratory Disease

Lebold

Jacoby

Drake

2016

Transfus Med Hemother

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Allergic asthma and allergic rhinitis are inflammatory diseases of the respiratory tract characterized by an excessive type-2 T helper cell (Th2) immune response. Toll-like receptor 7 (TLR7) is a single-stranded viral RNA receptor expressed in the airway that initiates a Th1 immune response and has garnered interest as a novel therapeutic target for treatment of allergic airway diseases. In animal models, synthetic TLR7 agonists reduce airway hyperreactivity, eosinophilic inflammation, and airway remodeling while decreasing Th2-associated cytokines. Furthermore, activation of TLR7 rapidly relaxes airway smooth muscle via production of nitric oxide. Thus, TLR7 has dual bronchodilator and anti-inflammatory effects. Two TLR7 ligands with promising pharmacologic profiles have entered clinical trials for the treatment of allergic rhinitis. Moreover, TLR7 agonists are potential antiviral therapies against respiratory viruses. TLR7 agonists enhance influenza vaccine efficacy and also reduce viral titers when given during an active airway infection. In this review, we examine the current data supporting TLR7 as a therapeutic target in allergic airway diseases.

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Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

Cited by 70 publications

References 31 publications

Extracellular RNA Sensing by Pattern Recognition Receptors

Extracellular RNA Sensing by Pattern Recognition Receptors

TLR7 Engagement on Dendritic Cells Enhances Autoreactive Th17 Responses via Activation of ERK

Toll-Like Receptor 7-Targeted Therapy in Respiratory Disease

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