Granulocyte functions are independent of arginine availability
Granulocyte functions are independent of arginine availability
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DOI：
10.1189/jlb.3ab0214-082r
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发表时间：
2014-12-01
影响因子：
5.5
通讯作者：
Munder, Markus
中科院分区：
文献类型：
--
作者：
Kapp, Katharina;Pruefer, Steve;Munder, Markus
在没有细胞外精氨酸的情况下，粒细胞活力、吞噬作用、IL-8 分泌、趋化性和抗真菌活性完全保留。通过骨髓细胞精氨酸酶消耗精氨酸与癌症或慢性炎症期间适应性免疫系统的抑制密切相关。另一方面，精氨酸消耗正在被开发为一种新型的抗肿瘤代谢策略，以剥夺精氨酸营养缺陷型癌细胞的这种氨基酸。在人体免疫细胞中，精氨酸酶主要在PMNs中组成型表达。因此，我们从健康供体中纯化了人类原代中性粒细胞，并分析了精氨酸缺乏情况下中性粒细胞作为主要先天效应细胞和精氨酸酶生产者的功能。我们证明，体外精氨酸的缺乏不会损害人 PMN 的活力、激活诱导的 IL-8 合成、趋化性、吞噬作用、ROS 的产生和杀菌活性。此外，在肺侵袭性曲霉病小鼠模型中，通过 ADI-PEG20 体内深度药理精氨酸消耗并不会抑制 PMN 功能； PMN 侵入肺部、激活、烟曲霉依赖 PMN 的成功清除以及小鼠的存活均没有受到损害。这些新发现增加了对炎症相关精氨酸消耗期间免疫的更好理解，并且对于开发精氨酸消耗作为抗代谢肿瘤疗法也很重要。
Granulocyte viability, phagocytosis, IL-8 secretion, chemotaxis, and antifungal activity are completely preserved in the absence of extracellular arginine. Arginine depletion via myeloid cell arginase is critically involved in suppression of the adaptive immune system during cancer or chronic inflammation. On the other hand, arginine depletion is being developed as a novel anti-tumor metabolic strategy to deprive arginine-auxotrophic cancer cells of this amino acid. In human immune cells, arginase is mainly expressed constitutively in PMNs. We therefore purified human primary PMNs from healthy donors and analyzed PMN function as the main innate effector cell and arginase producer in the context of arginine deficiency. We demonstrate that human PMN viability, activation-induced IL-8 synthesis, chemotaxis, phagocytosis, generation of ROS, and fungicidal activity are not impaired by the absence of arginine in vitro. Also, profound pharmacological arginine depletion in vivo via ADI-PEG20 did not inhibit PMN functions in a mouse model of pulmonary invasive aspergillosis; PMN invasion into the lung, activation, and successful PMN-dependent clearance of Aspergillus fumigatus and survival of mice were not impaired. These novel findings add to a better understanding of immunity during inflammation-associated arginine depletion and are also important for the development of therapeutic arginine depletion as anti-metabolic tumor therapy.