Ottina Eleonora, Lyberg Katarina, Sochalska Maja, Villunger Andreas, Nilsson Gunnar P
Division of Developmental Immunology, Biocenter, Medical University Innsbruck, A-6020 Innsbruck, Austria; and.
Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska Institute and Karolinska University Hospital, S-17176 Stockholm, Sweden.
J Immunol. 2015 Feb 1;194(3):1316-22. doi: 10.4049/jimmunol.1400637. Epub 2014 Dec 29.
Many forms of hypersensitivity reactions and allergic responses depend on deregulated mast cell activity. Several reports suggested that the antiapoptotic Bcl-2 family protein Bcl2a1/Bfl-1/A1 plays a critical role in mast cell survival upon activation. However, its in vivo relevance is poorly understood because of quadruplication of the Bcl2a1 gene locus in mice, hindering conventional knockout studies. In this study, we used a mouse model allowing traceable constitutive knockdown of all A1 isoforms expressed in the hematopoietic system by RNA interference. Knockdown of A1 reduced mast cell numbers in the skin and impaired connective tissue-like mast cell survival upon FcεRI-mediated activation in vitro. In contrast, A1 was dispensable for mucosa-like mast cell differentiation and survival. Moreover, knockdown of A1 prevented IgE-mediated passive systemic and cutaneous anaphylaxis in vivo. Our findings demonstrate that A1 is essential for the homeostasis of connective tissue mast cells, identifying A1 as a possible therapeutic target for therapy of certain types of mast cell-driven allergy symptoms.
多种形式的超敏反应和过敏反应都依赖于失调的肥大细胞活性。有几份报告表明，抗凋亡的Bcl-2家族蛋白Bcl2a1/Bfl-1/A1在肥大细胞激活后的存活中起关键作用。然而，由于小鼠中Bcl2a1基因座的四重复制，阻碍了传统的基因敲除研究，其在体内的相关性仍知之甚少。在本研究中，我们使用了一种小鼠模型，通过RNA干扰可追踪地组成性敲低造血系统中表达的所有A1亚型。敲低A1可减少皮肤中的肥大细胞数量，并损害FcεRI介导的体外激活后结缔组织样肥大细胞的存活。相反，A1对于粘膜样肥大细胞的分化和存活是可有可无的。此外，敲低A1可在体内预防IgE介导的被动全身和皮肤过敏反应。我们的研究结果表明，A1对于结缔组织肥大细胞的稳态至关重要，确定A1为治疗某些类型肥大细胞驱动的过敏症状的可能治疗靶点。
