活性型レセプターLMIR4の生体内における機能解析

学位の種別:課程博士University of Tokyo(東京大学

Jingmen tick virus : a tick-borne virus with unique features.

非分節化ゲノムのフラビウイルスに分類されながら、分節化したウイルスゲノムを持つingmenvirusは、昆虫及び脊椎動物に感染するアルボウイルスという性質のみならず、ゲノム構造の進化と粒子の多成分性による感染という、ウイルス学上重要な問題に対しても新しい視点を与えてくれるユニークな特徴を持っている。本稿ではJingmenvirusの中でも、このウイルス発見の端緒となったJingmen tick virusを中心にウイルス学的な特徴について解説した。The discovery of Jingmenvirus, which encodes closely related flavivirus-like enzymes but possesses segmented +ssRNA genomes, sparked significant debate regarding the evolutionary pathways leading to the creation of such viruses. This review outlines the distinctive features of Jingmenviruses, with a particular focus on the Jingmen tick virus—an arbovirus transmitted by ticks, posing potential risks as a human infectious agent.departmental bulletin pape

Intranasal administration of ceramide liposome suppresses allergic rhinitis by targeting CD300f in murine models

Abstract Allergic rhinitis (AR) is caused by type I hypersensitivity reaction in the nasal tissues. The interaction between CD300f and its ligand ceramide suppresses immunoglobulin E (IgE)-mediated mast cell activation. However, whether CD300f inhibits the development of allergic rhinitis (AR) remains elusive. We aimed to investigate the roles of CD300f in the development of AR and the effectiveness of intranasal administration of ceramide liposomes on AR in murine models. We used ragweed pollen-induced AR models in mice. Notably, CD300f deficiency did not significantly influence the ragweed-specific IgE production, but increased the frequency of mast cell-dependent sneezing as well as the numbers of degranulated mast cells and eosinophils in the nasal tissues in our models. Similar results were also obtained for MCPT5-exprssing mast cell-specific loss of CD300f. Importantly, intranasal administration of ceramide liposomes reduced the frequency of sneezing as well as the numbers of degranulated mast cells and eosinophils in the nasal tissues in AR models. Thus, CD300f–ceramide interaction, predominantly in mast cells, alleviates the symptoms and progression of AR. Therefore, intranasal administration of ceramide liposomes may be a promising therapeutic approach against AR by targeting CD300f

ダニ媒介性ウイルスJingmen tick virusが提起するウイルス学上の問題について

非分節化ゲノムのフラビウイルスに分類されながら、分節化したウイルスゲノムを持つingmenvirusは、昆虫及び脊椎動物に感染するアルボウイルスという性質のみならず、ゲノム構造の進化と粒子の多成分性による感染という、ウイルス学上重要な問題に対しても新しい視点を与えてくれるユニークな特徴を持っている。本稿ではJingmenvirusの中でも、このウイルス発見の端緒となったJingmen tick virusを中心にウイルス学的な特徴について解説した。The discovery of Jingmenvirus, which encodes closely related flavivirus-like enzymes but possesses segmented +ssRNA genomes, sparked significant debate regarding the evolutionary pathways leading to the creation of such viruses. This review outlines the distinctive features of Jingmenviruses, with a particular focus on the Jingmen tick virus—an arbovirus transmitted by ticks, posing potential risks as a human infectious agent

Staphylococcus aureus δ-toxin present on skin promotes the development of food allergy in a murine model

BackgroundPatients with food allergy often suffer from atopic dermatitis, in which Staphylococcus aureus colonization is frequently observed. Staphylococcus aureus δ-toxin activates mast cells and promotes T helper 2 type skin inflammation in the tape-stripped murine skin. However, the physiological effects of δ-toxin present on the steady-state skin remain unknown. We aimed to investigate whether δ-toxin present on the steady-state skin impacts the development of food allergy.Material and methodsThe non-tape-stripped skins of wild-type, KitW-sh/W-sh, or ST2-deficient mice were treated with ovalbumin (OVA) with or without δ-toxin before intragastric administration of OVA. The frequency of diarrhea, numbers of jejunum or skin mast cells, and serum levels of OVA-specific IgE were measured. Conventional dendritic cell 2 (cDC2) in skin and lymph nodes (LN) were analyzed. The cytokine levels in the skin tissues or culture supernatants of δ-toxin-stimulated murine keratinocytes were measured. Anti-IL-1α antibody-pretreated mice were analyzed.ResultsStimulation with δ-toxin induced the release of IL-1α, but not IL-33, in murine keratinocytes. Epicutaneous treatment with OVA and δ-toxin induced the local production of IL-1α. This treatment induced the translocation of OVA-loaded cDC2 from skin to draining LN and OVA-specific IgE production, independently of mast cells and ST2. This resulted in OVA-administered food allergic responses. In these models, pretreatment with anti-IL-1α antibody inhibited the cDC2 activation and OVA-specific IgE production, thereby dampening food allergic responses.ConclusionEven without tape stripping, δ-toxin present on skin enhances epicutaneous sensitization to food allergen in an IL-1α-dependent manner, thereby promoting the development of food allergy

Characterization of Leukocyte Mono-immunoglobulin-like Receptor 7 (LMIR7)/CLM-3 as an Activating Receptor: ITS SIMILARITIES TO AND DIFFERENCES FROM LMIR4/CLM-5*

Here we characterize leukocyte mono-Ig-like receptor 7 (LMIR7)/CLM-3 and compare it with an activating receptor, LMIR4/CLM-5, that is a counterpart of an inhibitory receptor LMIR3/CLM-1. LMIR7 shares high homology with LMIR4 in the amino acid sequences of its Ig-like and transmembrane domains. Flow cytometric analysis demonstrated that LMIR4 was predominantly expressed in neutrophils, whereas LMIR7 was highly expressed in mast cells and monocytes/macrophages. Importantly, LMIR7 engagement induced cytokine production in bone marrow-derived mast cells (BMMCs). Although FcRγ deficiency did not affect surface expression levels of LMIR7, it abolished LMIR7-mediated activation of BMMCs. Consistently we found significant interaction of LMIR7-FcRγ, albeit with lower affinity compared with that of LMIR4-FcRγ. Our results showed that LMIR7 transmits an activating signal through interaction with FcRγ. In addition, like LMIR4, LMIR7 synergizes with TLR4 in signaling. Analysis of several chimera receptors composed of LMIR4 and LMIR7 revealed these findings: 1) the transmembrane of LMIR7 with no charged residues maintained its surface expression at high levels in the absence of FcRγ; 2) the extracellular juxtamembrane region of LMIR7 had a negative effect on its surface expression levels; and 3) the strong interaction of LMIR4 with FcRγ depended on the extracellular juxtamembrane region as well as the transmembrane domain of LMIR4. Thus, LMIR7 shares similarities with LMIR4, although they are differentially regulated in their distribution, expression, and function