IL-17 mediates immunopathology in the absence of IL-10 following Leishmania major infection.
IL-17 mediates immunopathology in the absence of IL-10 following Leishmania major infection.
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DOI：
10.1371/journal.ppat.1003243
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发表时间：
2013-03
期刊：
影响因子：
6.7
通讯作者：
Scott P
中科院分区：
文献类型：
--
作者：
Gonzalez-Lombana C;Gimblet C;Bacellar O;Oliveira WW;Passos S;Carvalho LP;Goldschmidt M;Carvalho EM;Scott P
利什曼病，由原生动物寄生虫利什曼原虫感染引起，包括广泛的临床表现，从愈合的皮肤病变到致命的内脏感染。皮肤利什曼病的一种特别严重的形式，称为粘膜利什曼病，表现出降低的IL-10水平和夸大的炎症反应，使疾病持续存在。使用小鼠利什曼病模型，我们研究了当IL-10介导的调节不存在时，哪些细胞因子导致病理学增加。缺乏IL-10调节的大型利什曼原虫感染的C57 BL/6小鼠比对照组发生更大的病变，但寄生虫较少。IFN-γ和IL-17水平在缺乏对IL-10应答能力的小鼠中显著升高。IFN-γ促进单核细胞浸润增加，而IL-17促进中性粒细胞增加。然而，令人惊讶的是，我们发现IFN-γ并没有导致病理学的增加，而是调节了IL-17的反应。因此，阻断IFN-γ导致IL-17、中性粒细胞和疾病的显著增加。类似地，来自利什曼病患者的细胞的IL-17的产生也受到IL-10和IFN-γ的调节。其他研究发现，IL-1受体是IL-17应答和病理学增加所必需的。因此，我们认为调节IL-17（可能通过下调IL-1β）可能是控制利什曼病免疫病理学的一种有用方法。利什曼病是一种由白蛉传播的热带疾病，可引起内脏和皮肤病变。在人类中，皮肤利什曼病的最严重形式是粘膜形式，导致鼻和口腔粘膜的毁容病变。为什么这些患者发展为严重的疾病尚不清楚。然而，已知严重的疾病不是由于大量寄生虫，而是由于不受控制的炎症反应，包括IFN-γ和IL-17的产生增加。在这里，我们使用利什曼病的小鼠模型来确定参与这种病理学的因素，并发现感染利什曼原虫的小鼠在缺乏IL-10或IL-10信号传导的情况下发生严重病变，并且与患者相似，含有高水平的IFN-γ和IL-17。虽然这两种细胞因子都具有诱导病理学的潜力，但我们发现IL-17是在不存在IL-10调节的情况下观察到的严重病理学的原因，此外，在不存在IFN-γ的情况下，IL-17水平更高，病理学更严重。因此，我们的研究表明，IL-17，而不是IFN-γ，是一个强有力的候选人被靶向的战略，以控制严重的免疫病理学观察粘膜利什曼病患者。
Leishmaniasis, resulting from infection with the protozoan parasite Leishmania, consists of a wide spectrum of clinical manifestations, from healing cutaneous lesions to fatal visceral infections. A particularly severe form of cutaneous leishmaniasis, termed mucosal leishmaniasis, exhibits decreased IL-10 levels and an exaggerated inflammatory response that perpetuates the disease. Using a mouse model of leishmaniasis, we investigated what cytokines contribute to increased pathology when IL-10-mediated regulation is absent. Leishmania major infected C57BL/6 mice lacking IL-10 regulation developed larger lesions than controls, but fewer parasites. Both IFN-γ and IL-17 levels were substantially elevated in mice lacking the capacity to respond to IL-10. IFN-γ promoted an increased infiltration of monocytes, while IL-17 contributed to an increase in neutrophils. Surprisingly, however, we found that IFN-γ did not contribute to increased pathology, but instead regulated the IL-17 response. Thus, blocking IFN-γ led to a significant increase in IL-17, neutrophils and disease. Similarly, the production of IL-17 by cells from leishmaniasis patients was also regulated by IL-10 and IFN-γ. Additional studies found that the IL-1 receptor was required for both the IL-17 response and increased pathology. Therefore, we propose that regulating IL-17, possibly by downregulating IL-1β, may be a useful approach for controlling immunopathology in leishmaniasis. Leishmaniasis is a tropical disease transmitted by sand flies that causes visceral and cutaneous lesions. In humans, the most severe form of cutaneous leishmaniasis is the mucosal form, causing disfiguring lesions in the nasal and oral mucosa. Why these patients develop severe disease is not clear. It is known, however, that the severe disease is not due to an overwhelming number of parasites, but rather appears to be due to an uncontrolled inflammatory response that includes elevated production of IFN-γ and IL-17. Here, we used a murine model of leishmaniasis to identify the factors involved in this pathology, and found that mice infected with Leishmania major developed severe lesions in the absence of IL-10 or IL-10 signaling, and similar to patients, contained high levels of IFN-γ and IL-17. While both of these cytokines have the potential to induce pathology, we found that IL-17 was responsible for the severe pathology seen in the absence of IL-10 regulation, and furthermore that IL-17 levels were higher and pathology greater in the absence of IFN-γ. Thus, our study suggests that IL-17, but not the IFN-γ, is a strong candidate to be targeted in strategies to control the severe immunopathology observed in mucosal leishmaniasis patients.
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影响因子：
30.5
作者：
Acosta-Rodriguez, Eva V.;Napolitani, Giorgio;Sallusto, Federica
通讯作者：
Sallusto, Federica
DOI：
10.4269/ajtmh.2007.77.854
发表时间：
2007-11-01
影响因子：
3.3
作者：
Bomfim, Gloria;Andrade, Bruno B.;Barral, Aldina
通讯作者：
Barral, Aldina
白介素10在抑制肠炎的调节T细胞功能中的重要作用。
影响因子：
15.3
作者：
Asseman, C;Mauze, S;Leach, M W;Coffman, R L;Powrie, F
通讯作者：
Powrie, F
白介素（IL）-10在愈合后皮肤中持续的持久性以及抗IL-10受体抗体对无菌治疗的治疗潜力的作用。
DOI：
10.1084/jem.194.10.1497
发表时间：
2001-11-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Belkaid Y;Hoffmann KF;Mendez S;Kamhawi S;Udey MC;Wynn TA;Sacks DL
通讯作者：
Sacks DL
影响因子：
--
作者：
Cohen, S;Hurd, E;McCabe, D
通讯作者：
McCabe, D