1-B-S08-1
炎症後期に出現するM2マクロファージは高い死細胞貪食能を持ち、好塩基球依存的皮膚アレルギー炎症の収束に寄与する
Highly efferocytic M2 macrophages are generated at the termination stage of basophil-dependent skin allergy and dampen the inflammation
〇三宅 健介1、伊藤 潤哉1、高橋 和総1、中林 潤2、七野 成之3、烏山 一1
Kensuke Miyake1, Junya Ito1, Kazufusa Takahashi1, Jun Nakabayashi2, Shigeyuki Shichino3, Hajime Karasuyama1
1東京医科歯科大・高等研究院・炎症・感染・免疫研究室、2東京医科歯科大・統合教育機構、3東京理科大・生命医科学研究所
1Adv. Res. Inst., Tokyo Med. Dent. Univ., 2Inst. Education, Tokyo Med. Dent. Univ., 3Res. Inst. Biol. Sci., Tokyo Univ. of Sci.
Basophils play critical roles in the development of delayed-onset skin allergic inflammation in mice (IgE-CAI model). Importantly, they also contribute to the resolution of allergic inflammation by promoting the generation of M2 macrophages. However, it remains unclear how M2 macrophages suppress excess inflammation. To address this, we conducted single-cell RNA-seq (scRNA-seq) analysis of the IgE-CAI skin lesion. scRNA-seq analysis identified two distinct M2 macrophage populations, namely early and late M2 macrophages, in IgE-CAI skin lesion. The former population was preferentially observed at the peak of inflammation (3 days after allergen challenge), whereas the latter one at the termination phase of inflammation (5 days). Gene ontology analysis revealed that genes associated with phagocytosis were enriched in late M2 macrophages. In particular, late M2 macrophages displayed upregulated expression of Gas6 and Mertk, key genes responsible for phagocytic clearance of apoptotic cells. Of note, MERTK inhibitor significantly aggravated ear swelling and accumulation of inflammatory cells in the skin lesion. Taken together, scRNA-seq identified M2 macrophages that display high capacity of dead cell clearance and contribute to the resolution of IgE-CAI.
1-B-S08-2
P2X4イオンチャネル型受容体を介した肥満細胞機能およびアレルギー反応のプリン作動性調節
Purinergic regulation of mast cell function and allergic response via ionotropic P2X4 receptors
〇吉田 一貴、伊藤 政明、松岡 功
Kazuki Yoshida, Masa-Aki Ito, Isao Matsuoka
高崎健康福祉大・薬
Lab. Pharmacol., Fact. Pharm, Takasaki Univ. Health and Welfare
Mast cells are highly reactive and release a variety of mediators that cause allergic and inflammatory reactions. The most well-known mechanism of mast cell activation is antigen-induced aggregation of IgE-binding FcεRI complexes on the cell surface. The IgE-dependent mast cell activation is regulated by various humoral factors that lower the threshold for antigen-mediated activation, exacerbating allergic reactions. Recently, we found that extracellular ATP is an important factor in enhancing mast cell response to weak signals elicited by IgE-dependent as well as -independent mechanisms. Mast cells express many functional P2 receptors, but ATP-induced synergistic mast cell activation to antigens and G protein-coupled receptor agonists, such as PGE2, adenosine and compound 48/80 were exclusively mediated by ionotropic P2X4 receptors. In addition, genetic and pharmacological inhibition of P2X4 receptor improved the IgE-dependent and -independent anaphylactic responses in vivo. Since ATP is a ubiquitous intercellular mediator that coexists with other chemical mediators, P2X4 receptor signal should play an important role in mast cell-dependent allergic reaction in vivo. In this symposium, we will introduce the unique effects of P2X4 receptor signals on various mast cell activation mechanisms found in our laboratory.
1-B-S08-3
IgE依存的・非依存的なマスト細胞の活性化とアレルギー応答の制御機序
The regulatory mechanisms of IgE-dependent and independent mast cell activation and allergic responses
〇北浦 次郎
Kitaura Jiro
順天堂大・医・アトピー疾患研究センター
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Mast cells play a central role in IgE-dependent allergic responses. Engagement of antigen-specific IgE-bound FceRI with the same antigen induces mast cell degranulation, leading to the immediate hypersensitivity reaction. On the other hand, stimulation with cationic drugs (e.g., compound 48/80) induces IgE-independent degranulation of connective tissue mast cells via Mrgprb2, the murine homolog of MRGPRX2, leading to pseudo-allergic reaction. However, an inhibitory receptor CD300f down-regulates the excessive activation of mast cells in vivo. In fact, both FceRI-mediated anaphylactic responses and Mrgprb2-mediated pseudo-allergic responses are enhanced in CD300f-deficient mice compared to wild-type mice. We have previously identified ceramide as a ligand for CD300f. Consistently, administration of ceramide liposomes, prepared by using an extruder, inhibits both anaphylactic and pseudo-allergic responses in mice. In addition, we recently developed a new method to generate stable ceramide liposomes and demonstrated that intranasal administration of newly-generated ceramide liposomes inhibits ragweed pollen-induced allergic rhinitis in murine models. Thus, intranasal administration of ceramide liposomes will be a useful therapeutic strategy against allergic rhinitis.
1-B-S08-4
GPCRを介するマスト細胞活性化の制御機構
Regulation of mast cell activation mediated by G protein-coupled receptors
〇田中 智之
Satoshi Tanaka
京都薬科大・薬・薬理学
Dept. Pharmacol., Kyoto Pharmaceut. Univ.
Mast cells are strategically distributed as sentinels, which alert the immune system upon infiltration of foreign materials and pathogens. Mast cells trigger inflammatory responses by releasing their pro-inflammatory mediators. Some materials are recognized by IgE and cross-link the FceRI and others directly activate surface membrane receptors expressed in mast cells. Although it long remained to be clarified how mast cells are activated in the latter cases, a series of recent studies have revealed that Mas-related G protein-coupled receptors (Mrgprs) should play critical roles in IgE-independent degranulation of mast cells. On the other hand, large-scale ligand screenings suggested that an orphan G protein-coupled receptor (GPCR), GPR35, should be the candidate for the target molecules of mast cell stabilizers, such as disodium cromoglycate. Here I present our recent progress in the investigation of the roles of various Mrgpr family receptors and GPR35 expressed in murine mast cells. Development of the antagonists of Mrgprs and the agonists of GPR35 might open up novel therapeutic approaches for inflammatory diseases, in which tissue mast cells play a primary role.