Upregulation of retinal dehydrogenase 2 in alternatively activated macrophages during retinoid-dependent type-2 immunity to helminth infection in mice.
Upregulation of retinal dehydrogenase 2 in alternatively activated macrophages during retinoid-dependent type-2 immunity to helminth infection in mice.
复制标题
DOI：
10.1371/journal.ppat.1002883
复制
发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Loke P
中科院分区：
文献类型：
--
作者：
Broadhurst MJ;Leung JM;Lim KC;Girgis NM;Gundra UM;Fallon PG;Premenko-Lanier M;McKerrow JH;McCune JM;Loke P
虽然维生素A代谢物视黄酸（RA）在免疫功能中起着关键作用，但对感染期间RA的合成知之甚少。在这里，我们表明，视网膜脱落酶（Raldh），所需的RA的合成，诱导类维生素A依赖的2型免疫反应引起的曼氏血吸虫感染，但不是在类维生素A独立的抗病毒免疫反应。维生素A缺乏的小鼠在对S. mansoni，但保留正常的LCMV特异性TH 1反应。原位成像、活体成像和分选纯化的组合显示，交替激活的巨噬细胞（AAMφ）在S.曼氏感染。IL-4诱导体外骨髓源性巨噬细胞和体内腹腔巨噬细胞中Raldh 2的表达。最后，体内衍生的AAMφ具有增强的通过RA依赖性机制诱导CD 4+细胞中Foxp 3表达的能力，特别是与TGF-β组合。在感染过程中调节Raldh酶是病原体特异性的，并反映了效应反应过程中对RA的不同要求。具体而言，AAMφ是蠕虫感染期间RA合成的可诱导来源和在调节免疫应答中可能重要的TH 2应答。维生素A缺乏症是一个主要的全球健康问题，它增加了传染病的发病率和死亡率。维生素A被免疫系统利用，它必须代谢成视黄酸（RA），其活性形式。RA是T细胞活性的关键决定因素。然而，其在感染期间对保护性免疫的贡献知之甚少，在这种情况下其合成的调节也是如此。我们研究了免疫细胞对蠕虫感染和病毒感染的RA合成。虽然肠道T细胞反应是维生素A依赖性在这两种感染，只有T细胞反应引起的蠕虫感染是维生素A依赖性的肝脏。与这一发现相一致的是，在蠕虫感染期间，RA合成所需的酶由募集到肝脏的炎性细胞表达，而不是病毒。我们确定了替代激活的巨噬细胞作为响应蠕虫感染的免疫细胞内RA合成的来源，并发现它们可以诱导调节性T细胞。我们的研究结果提供了一个更好的理解，在感染期间的维生素A的利用，并表明，RA合成是一个诱导的保护性免疫的组成部分。
Although the vitamin A metabolite retinoic acid (RA) plays a critical role in immune function, RA synthesis during infection is poorly understood. Here, we show that retinal dehydrogenases (Raldh), required for the synthesis of RA, are induced during a retinoid-dependent type-2 immune response elicited by Schistosoma mansoni infection, but not during a retinoid-independent anti-viral immune response. Vitamin A deficient mice have a selective defect in TH2 responses to S. mansoni, but retained normal LCMV specific TH1 responses. A combination of in situ imaging, intra-vital imaging, and sort purification revealed that alternatively activated macrophages (AAMφ) express high levels of Raldh2 during S. mansoni infection. IL-4 induces Raldh2 expression in bone marrow-derived macrophages in vitro and peritoneal macrophages in vivo. Finally, in vivo derived AAMφ have an enhanced capacity to induce Foxp3 expression in CD4+ cells through an RA dependent mechanism, especially in combination with TGF-β. The regulation of Raldh enzymes during infection is pathogen specific and reflects differential requirements for RA during effector responses. Specifically, AAMφ are an inducible source of RA synthesis during helminth infections and TH2 responses that may be important in regulating immune responses. Vitamin A deficiency, a major global health concern, increases morbidity and death due to infectious diseases. For vitamin A to be utilized by the immune system, it must be metabolized into retinoic acid (RA), its active form. RA is a key determinant of T cell activity. However, its contribution to protective immunity during infection is poorly understood, as is the regulation of its synthesis in this context. We examined RA synthesis by immune cells responding to helminth infection and virus infection. While intestinal T cell responses were vitamin A-dependent during both infections, only T cell responses elicited by helminth infection were vitamin A-dependent in the liver. Consistent with this finding, the enzymes necessary for RA synthesis were expressed by inflammatory cells recruited to the liver during helminth, but not virus, infection. We identified alternatively-activated macrophages as a source of RA synthesis within immune cells responding to helminth infection and find that they can induce regulatory T cells. Our findings provide a better understanding of vitamin A utilization during infection and demonstrate that RA synthesis is an inducible component of protective immunity.
登录
查看更多内容
影响因子：
32.4
作者：
Hall JA;Cannons JL;Grainger JR;Dos Santos LM;Hand TW;Naik S;Wohlfert EA;Chou DB;Oldenhove G;Robinson M;Grigg ME;Kastenmayer R;Schwartzberg PL;Belkaid Y
通讯作者：
Belkaid Y
影响因子：
32.4
作者：
Hall JA;Grainger JR;Spencer SP;Belkaid Y
通讯作者：
Belkaid Y
影响因子：
32.4
作者：
Hill JA;Hall JA;Sun CM;Cai Q;Ghyselinck N;Chambon P;Belkaid Y;Mathis D;Benoist C
通讯作者：
Benoist C
影响因子：
30.5
作者：
Denning, Timothy L.;Wang, Yi-Chong;Pulendran, Bali
通讯作者：
Pulendran, Bali
影响因子：
5.1
作者：
Duester, G;Mic, FA;Molotkov, A
通讯作者：
Molotkov, A