Cationic amino acid transporter-2 regulates immunity by modulating arginase activity.
Cationic amino acid transporter-2 regulates immunity by modulating arginase activity.
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DOI：
10.1371/journal.ppat.1000023
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发表时间：
2008-03-14
期刊：
影响因子：
6.7
通讯作者：
Wynn TA
中科院分区：
文献类型：
--
作者：
Thompson RW;Pesce JT;Ramalingam T;Wilson MS;White S;Cheever AW;Ricklefs SM;Porcella SF;Li L;Ellies LG;Wynn TA
阳离子氨基酸转运蛋白（CAT）是NOS 2和ARG 1活性的重要调节因子，因为它们调节L-精氨酸的可用性。然而，它们在感染后Th 1/Th 2效应子功能发展中的作用尚未研究。在这里，我们通过研究两种感染性疾病模型，其特征在于极化的Th 1或Th 2型反应的发展来剖析CAT 2的功能。我们发现CAT 2 −/−小鼠对Th 1诱导病原体弓形虫明显更敏感。虽然T.弓形虫感染的CAT 2 −/−小鼠产生更强的IFN-γ反应，一氧化氮（NO）的产生显著受损，这有助于其增强的易感性。相比之下，感染Th 2诱导病原体曼氏血吸虫的CAT 2 −/−小鼠对感染的易感性没有变化，尽管它们死于血吸虫病的速度加快。肉芽肿形成和纤维化，Th 2细胞因子调节的病理特征，也加剧，即使他们的Th 2反应降低。最后，虽然IL-13阻断在野生型小鼠中非常有效，但CAT 2 −/−小鼠的纤维化发展在很大程度上是IL-13非依赖性的。相反，在体外和体内，恶化的病理学与成纤维细胞和替代活化的巨噬细胞中的脱氢酶活性增加相关。因此，通过控制NOS 2和CAT酶活性，CAT 2作为免疫力的有效调节剂发挥作用。最近对氨基转运蛋白Slc 7a 2缺陷小鼠（CAT 2）进行的研究表明，巨噬细胞中的NOS 2活性受CAT 2调节。NOS 2合成一氧化氮，调节许多重要的活动，包括对感染性生物体的抵抗，肿瘤的发展和自身免疫性疾病。它还与精氨酸酶-1（Arg 1）竞争共同底物L-精氨酸。然而，CAT 2在Arg 1活性调节中的作用以前没有被研究过。因此，我们用蠕虫寄生虫曼氏血吸虫（Schistosoma mansoni）或原生动物病原体刚地弓形虫（Toxoplasma gondii）感染CAT 2缺陷小鼠，这两种生物体引发高度不同的宿主免疫反应。引人注目的是，感染S. mansoni，CAT 2 −/−小鼠的肝脏出现了寄生虫卵诱导的病变，比野生型大3至4倍，肝纤维化（严重血吸虫病的一个特征）加剧，表明在没有CAT 2的情况下疾病普遍恶化。CAT 2 −/−小鼠也更容易受到T。弓形虫感染，证明CAT 2是保护性细胞介导的免疫力的发展至关重要。因此，这些研究将CAT 2鉴定为宿主免疫应答的强大调节剂，这可能对各种感染性、炎症性和自身免疫性疾病具有重要意义。
Cationic amino acid transporters (CAT) are important regulators of NOS2 and ARG1 activity because they regulate L-arginine availability. However, their role in the development of Th1/Th2 effector functions following infection has not been investigated. Here we dissect the function of CAT2 by studying two infectious disease models characterized by the development of polarized Th1 or Th2-type responses. We show that CAT2−/− mice are significantly more susceptible to the Th1-inducing pathogen Toxoplasma gondii. Although T. gondii infected CAT2−/− mice developed stronger IFN-γ responses, nitric oxide (NO) production was significantly impaired, which contributed to their enhanced susceptibility. In contrast, CAT2−/− mice infected with the Th2-inducing pathogen Schistosoma mansoni displayed no change in susceptibility to infection, although they succumbed to schistosomiasis at an accelerated rate. Granuloma formation and fibrosis, pathological features regulated by Th2 cytokines, were also exacerbated even though their Th2 response was reduced. Finally, while IL-13 blockade was highly efficacious in wild-type mice, the development of fibrosis in CAT2−/− mice was largely IL-13-independent. Instead, the exacerbated pathology was associated with increased arginase activity in fibroblasts and alternatively activated macrophages, both in vitro and in vivo. Thus, by controlling NOS2 and arginase activity, CAT2 functions as a potent regulator of immunity. Recent studies conducted with amino transporter Slc7a2-deficient mice (CAT2) demonstrated that NOS2 activity in macrophages is regulated by CAT2. NOS2, which synthesizes nitric oxide, regulates numerous important activities, including resistance to infectious organisms, tumor development, and autoimmune diseases. It also competes with the enzyme Arginase-1 (Arg1) for the common substrate L-arginine. However, the role CAT2 in the regulation of Arg1 activity has not been previously examined. Therefore, we infected CAT2-deficient mice with the helminth parasite Schistosoma mansoni or with the protozoan pathogen Toxoplasma gondii, two organisms that trigger highly divergent host immune responses. Strikingly, following infection with S. mansoni, CAT2−/− mice developed parasite egg–induced lesions in the liver that were 3 to 4 times larger than wild type and hepatic fibrosis (a feature of severe schistosomiasis) was exacerbated, indicating a general worsening of disease in the absence of CAT2. The CAT2−/− mice were also more susceptible to T. gondii infection, demonstrating that CAT2 is critical for the development of protective cell-mediated immunity. Thus, these studies identify CAT2 as a powerful regulator of host immune responses, which may have major implications for a variety of infectious, inflammatory, and autoimmune diseases.
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DOI：
10.1152/ajpheart.1998.274.1.h342
发表时间：
1998-01-01
影响因子：
4.8
作者：
Chang, CI;Liao, JC;Kuo, L
通讯作者：
Kuo, L
影响因子：
32.4
作者：
Kaplan, MH;Schindler, U;Grusby, MJ
通讯作者：
Grusby, MJ
影响因子：
4.4
作者：
Fallon, PG;Richardson, EJ;McKenzie, ANJ
通讯作者：
McKenzie, ANJ
影响因子：
7.4
作者：
BERGMAN, I;LOXLEY, R
通讯作者：
LOXLEY, R
影响因子：
5.5
作者：
Edwards, Justin P.;Zhang, Xia;Mosser, David M.
通讯作者：
Mosser, David M.