β-Defensins activate human mast cells via Mas-related gene X2.
β-Defensins activate human mast cells via Mas-related gene X2.
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DOI：
10.4049/jimmunol.1300023
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发表时间：
2013-07-01
期刊：
影响因子：
--
通讯作者：
Ali H
中科院分区：
文献类型：
--
作者：
Subramanian H;Gupta K;Lee D;Bayir AK;Ahn H;Ali H
人β-防御素（hBDs）在体外刺激大鼠腹膜肥大细胞脱颗粒，并在体内引起大鼠血管通透性增加。在这里，我们试图确定hBDs是否激活小鼠和人类肥大细胞，并描述其调节机制。hBD2和hBD3在体外不诱导小鼠腹膜或骨髓源性肥大细胞（BMMC）脱肉芽，在体内对血管通透性没有影响。相比之下，这些肽在人肥大细胞中诱导持续的Ca2+动员和大量的脱颗粒，hBD3更有效。百日毒（PTx）对hbd诱导的Ca2+动员没有影响，但La3+和2-氨基乙氧基二苯硼酸盐（2-APB）； IP3受体和瞬时受体电位（TRP）通道的双重抑制剂对这一反应产生了实质性的抑制。有趣的是，PTx、La3+或2-APB显著抑制hBDs诱导的脱粒。而人肥大细胞内源性表达G蛋白偶联受体（GPCR）；mas相关基因X2 （MrgX2）、大鼠嗜碱性白血病、RBL-2H3细胞和小鼠BMMCs则没有。沉默人肥大细胞中MrgX2的表达可抑制hbd诱导的脱颗粒，但对过敏毒素c3a诱导的反应无影响。此外，MrgX2在RBL-2H3和小鼠BMMCs中的异位表达使这些细胞对hBDs脱颗粒有反应。本研究表明，hBDs通过MrgX2激活人肥大细胞，MrgX2与可能涉及Gαq和Gαi的PTx敏感和不敏感信号通路结合，诱导脱颗粒。此外，小鼠肥大细胞对hBDs的脱颗粒具有抗性，这反映了这些细胞中MrgX2的缺失。
Human β-defensins (hBDs) stimulate degranulation in rat peritoneal mast cells in vitro and cause increased vascular permeability in rats in vivo. Here, we sought to determine if hBDs activate murine and human mast cells and to delineate the mechanisms of their regulation. hBD2 and hBD3 did not induce degranulation in murine peritoneal or bone marrow-derived mast cells (BMMC) in vitro and had no effect on vascular permeability in vivo. By contrast, these peptides induced sustained Ca2+ mobilization and substantial degranulation in human mast cells with hBD3 being more potent. Pertussis toxin (PTx) had no effect on hBD-induced Ca2+ mobilization but La3+ and 2-Aminoethoxydiphenyl borate (2-APB; a dual inhibitor of IP3 receptor and transient receptor potential (TRP) channels caused substantial inhibition of this response. Interestingly, degranulation induced by hBDs was substantially inhibited by PTx, La3+ or 2-APB. While human mast cells endogenously express G protein coupled receptor (GPCR); Mas-related gene X2 (MrgX2), rat basophilic leukemia, RBL-2H3 cells and murine BMMCs do not. Silencing the expression of MrgX2 in human mast cells inhibited hBD-induced degranulation but had no effect on anaphylatoxin C3a-induced response. Furthermore, ectopic expression of MrgX2 in RBL-2H3 and murine BMMCs rendered these cells responsive to hBDs for degranulation. This study demonstrates that hBDs activate human mast cells via MrgX2, which couples to both PTx sensitive and insensitive signaling pathways likely involving Gαq and Gαi to induce degranulation. Furthermore, murine mast cells are resistant to hBDs for degranulation and this reflect the absence of MrgX2 in these cells.
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