Malondialdehyde-acetaldehyde haptenated protein binds macrophage scavenger receptor(s) and induces lysosomal damage.
Malondialdehyde-acetaldehyde haptenated protein binds macrophage scavenger receptor(s) and induces lysosomal damage.
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DOI：
10.1016/j.intimp.2004.04.004
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发表时间：
2004-07
影响因子：
5.6
通讯作者：
M. Willis;L. Klassen;D. Carlson;C. Brouse;G. Thiele
中科院分区：
文献类型：
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作者：
M. Willis;L. Klassen;D. Carlson;C. Brouse;G. Thiele
有证据表明，蛋白质（半抗原）与丙二醛-乙醛（MAA）的化学修饰和对这些半抗原化蛋白质的免疫应答与酒精性肝病的发生和/或进展相关。实验上，用MAA修饰的蛋白质诱导抗体和T细胞应答，其由清道夫受体介导。此外，巨噬细胞已被证明在体外加工和呈递MAA-半抗原化蛋白中发挥重要作用。在体外，MAA修饰的蛋白质已被证明以剂量和细胞类型依赖性的方式诱导细胞凋亡和坏死。通过氧化应激修饰的天然配体，例如氧化LDL，同样地不仅引发抗体应答，而且通过在与清道夫受体结合和内化后破坏溶酶体而引起细胞死亡。因此，我们研究了结合，内化，和溶酶体的完整性在巨噬细胞系的MAA-半抗原化蛋白。我们首次证明，MAA-半抗原化的蛋白质优先结合的清道夫受体的巨噬细胞，内化的配体和穿梭它们的溶酶体。此外，MAA-半抗原化蛋白被证明与溶酶体完整性的快速剂量依赖性破坏相关，导致渗漏和半胱天冬酶激活。类似地，随着鸡蛋溶菌酶（HEL）-MAA浓度增加（>31.3 μg/ml），鉴定出细胞凋亡水平增加和G1/S细胞周期检查点抑制。本研究确定了MAA-半抗原化蛋白被代表性抗原呈递细胞摄取的机制，并可能描述了MAA-半抗原化蛋白诱导细胞死亡和诱导其对载体蛋白的免疫原性的步骤。
There is evidence that the chemical modification of proteins (haptens) with malondialdehyde–acetaldehyde (MAA) and the immune response to these haptenated proteins is associated with the initiation and/or progression of alcohol liver disease. Experimentally, proteins modified with MAA induce antibody and T cell responses, which are mediated by scavenger receptor(s). Moreover, macrophages have been shown to play an important role in processing and presenting MAA-haptenated proteins in vitro. In vitro, MAA-modified proteins have been shown to induce both apoptosis and necrosis in a dose- and cell-type-dependent manner. Natural ligands modified by oxidative stress, such as oxidized LDL, similarly initiate not only antibody responses, but also cause cell death by disrupting lysosomes after binding to scavenger receptors and internalization. We therefore investigated the binding, internalization, and lysosomal integrity in a macrophage cell line to a MAA-haptenated protein. We demonstrate for the first time that MAA-haptenated proteins are preferentially bound by scavenger receptors on macrophages, which internalize the ligands and shuttle them to lysosomes. Moreover, MAA-haptenated proteins are demonstrated to be associated with a rapid dose-dependent disruption in lysosomal integrity, resulting in leakage and caspase activation. Similarly, as hen egg lysozyme (HEL)–MAA concentrations increased (>31.3 μg/ml), increased levels of apoptosis and a G1/S cell cycle checkpoint inhibition were identified. This study identifies mechanisms by which MAA-haptenated proteins are taken up by a representative antigen-presenting cell and may delineate steps by which MAA-haptenated proteins induce cell death and induce their immunogenicity to the carrier protein.