Pathophysiological roles of basophils and mast cells in allergic inflammations

嗜碱性粒细胞和肥大细胞在过敏性炎症中的病理生理作用

• 批准号: 18380176
• 负责人: GOITSUKA Ryo
• 金额: $ 11.35万
• 依托单位: Tokyo University of Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18380176/
• 关键词: Allergy; mast cells; basophils; IgE receptor; signal transduction

Engagement of the high-affinity IgE receptor (FcεRI) on mast cells as well as basophils induces the release of preformed inflammatory mediators by degranulation and also the de novo synthesis and secretion of inflammatory cytokines, leading to an array of acute and chronic allergic symptoms. Two SLP-76 family adaptors, SLP-76 and MIST, are expressed in both mast cells and basophils, and both are involved in FcεRI -signaling. However, the functional redundancy and/or specificity of SLP-76 and MIST in this process remain unclear. In the present study, we intended to clarify the functional redundancy and/or specificity of SLP-76 and MIST in FcεRI-mediated allergic reactions by using mice deficient in MIST and/or SLP-76.FcεRI-induced degranulation was slightly and profoundly reduced in MIST- and SLP-76-deficient mast cells than in wild type cells, respectively. The residual degranulation detected in SLP-76-deficient cells was completely abrogated by the introduction of a MIST-deficiency. T … More o gain insight into the molecular basis for the functional difference between SLP-76 and MIST in FcεRI-signaling, we examined the mode of molecular interactions and membrane targeting of these two adaptors. SLP-76 associated with Grb2-related adaptor downstream of She (Gads) whereas MIST did not. However, when the Grb2-binding motif in MIST was replaced with a high-affinity RXXK SH3-binding motif from SLP-76, this mutant (MIST-GBF) gained the ability to associate with Gads. Although recruitment and cluster formation of wild type MIST at the antigen contact site were weaker than that observed for SLP-76, the MIST GBF mutant behaved like SLP-76 in terms of these FcεRI-induced changes. Furthermore, expression of MIST-GBF in mast cells enhanced FcεRI-mediated degranulation to a level comparable to that observed in SLP-76-expressing cells, indicating that the presence of the Gads-binding motif (RXXK) determines the functional dominance of SLP-76 over MIST in FcεRI-mediated mast cell activation.Since SLP-76 is constitutively but MIST is inducibly expressed in mast cells and basophils, these two SLP-76 family adaptors function as a basal essential regulator and an amplifier of FcεRI-mediated mast cell activation, respectively, in allergic reactions. Less

肥大细胞和嗜碱性粒细胞上的高亲和力 IgE 受体 (FcεRI) 的参与会通过脱颗粒诱导预先形成的炎症介质的释放，以及炎症细胞因子的从头合成和分泌，从而导致一系列急性和慢性过敏症状。两个 SLP-76 家族接头 SLP-76 和 MIST 在肥大细胞和嗜碱性粒细胞中表达，并且两者都参与 FcεRI 信号传导。然而，SLP-76 和 MIST 在此过程中的功能冗余和/或特异性仍不清楚。在本研究中，我们打算通过使用MIST和/或SLP-76缺陷的小鼠来阐明SLP-76和MIST在FcεRI介导的过敏反应中的功能冗余和/或特异性。在MIST和SLP-76缺陷的肥大细胞中，与野生型细胞相比，FcεRI诱导的脱粒分别轻微和显着减少。通过引入 MIST 缺陷，SLP-76 缺陷细胞中检测到的残留脱颗粒被完全消除。为了深入了解 SLP-76 和 MIST 在 FcεRI 信号传导中功能差异的分子基础，我们检查了这两种接头的分子相互作用和膜靶向模式。 SLP-76 与 She (Gads) 下游的 Grb2 相关接头相关，而 MIST 则不然。然而，当 MIST 中的 Grb2 结合基序被 SLP-76 中的高亲和力 RXXK SH3 结合基序取代时，该突变体 (MIST-GBF) 获得了与 Gads 结合的能力。尽管野生型 MIST 在抗原接触位点的募集和簇形成弱于 SLP-76 观察到的情况，但 MIST GBF 突变体在这些 FcεRI 诱导的变化方面表现得与 SLP-76 相似。此外，肥大细胞中 MIST-GBF 的表达将 FcεRI 介导的脱颗粒增强至与 SLP-76 表达细胞中观察到的水平相当，表明 Gads 结合基序 (RXXK) 的存在决定了在 FcεRI 介导的肥大细胞激活中 SLP-76 相对于 MIST 的功能优势。因为 SLP-76 是组成型的，但 MIST 是组成型的。 这两种 SLP-76 家族接头在肥大细胞和嗜碱性粒细胞中诱导表达，在过敏反应中分别充当 FcεRI 介导的肥大细胞激活的基础必需调节剂和放大器。较少的

项目成果

Chicken cathelicidin-B1, an antimicrobial guardian at the mucosal M cell gateway

• DOI: 10.1073/pnas.0707037104
• 发表时间: 2007-09-18
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Goitsuka, Ryo;Chen, Chen-Io H.;Cooper, Max D.
• 通讯作者: Cooper, Max D.

BASH-novel PKC-Raf-1 pathway of pre-BCR signaling induces κ gene rearrangement.

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• 发表时间: 2006
• 期刊: Blood 108
• 作者: Yamamoto;M.;Hayashi;K.;Nojima;T.;Matsuzaki;Y.;Kawano;Y.;Karasuyama;H.;Goitsuka;R.;Kitamura D.
• 通讯作者: Kitamura D.

BASH-novel RKC-Raf-1 pathway of pre-BCR signaling induces κ gene rearrangement

BASH 新型 RKC-Raf-1 前 BCR 信号通路诱导 κ 基因重排

• 发表时间: 2006
• 期刊: Blood 108
• 作者: Yamamoto;M.;et. al.
• 通讯作者: et. al.

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• 发表时间: 2007
• 作者: 檜山 綾子;他
• 通讯作者: 他

Distinct regulatory functions of SLP-76 and MIST in NK cell cytotoxicity and IFN-g production

SLP-76 和 MIST 在 NK 细胞毒性和 IFN-g 产生中的独特调节功能

• 发表时间: 2008
• 期刊: Int. Immunol (in press)
• 作者: Hidano;S.;Sasanuma;H.;Ohshima;K.;Seino;K-I.;Kumar;L.;Hayashi;K.;Hikida;M.;Kurosaki;T.;Taniguchi;M.;Geha;R. S.;Kitamura;D.;Goitsuka;R
• 通讯作者: R