Deletion of IL-4 receptor alpha on dendritic cells renders BALB/c mice hypersusceptible to Leishmania major infection.
Deletion of IL-4 receptor alpha on dendritic cells renders BALB/c mice hypersusceptible to Leishmania major infection.
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DOI：
10.1371/journal.ppat.1003699
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发表时间：
2013-10
期刊：
影响因子：
6.7
通讯作者：
Brombacher F
中科院分区：
文献类型：
--
作者：
Hurdayal R;Nieuwenhuizen NE;Revaz-Breton M;Smith L;Hoving JC;Parihar SP;Reizis B;Brombacher F
在BALB/c小鼠中，对细胞内寄生虫利什曼原虫感染的易感性主要是由辅助性T - 2 （Th2）反应的发展和白细胞介素(IL)-4和IL-13的产生驱动的，它们具有共同的受体亚基，IL-4受体α链（IL- 4r α）。虽然IL-4是Th2反应的主要诱导剂，但矛盾的是，已经证明外源性给予IL-4可以促进树突状细胞（DC） IL-12的产生并增强Th1的发育，如果在感染早期给予。为了进一步研究IL-4在体内感染过程中作用于DC的生物学量的相关性，在cd11c位点的控制下，利用cre/loxP系统通过基因靶向和位点特异性重组产生DC特异性IL-4Rα缺陷（CD11ccreIL-4Rα-/lox） BALB/c小鼠。CD11ccreIL-4Rα-/lox小鼠的树突状细胞和肺泡巨噬细胞中IL-4Rα的DNA、蛋白和功能表征均显示IL-4Rα表达减少。感染L. major后，CD11ccreIL-4Rα-/lox小鼠变得对疾病易感，表现为脚垫肿胀、坏死和寄生虫负担更早和增加，Th2细胞因子反应上调，2型抗体产生增加，巨噬细胞经典活化受损。CD11ccreIL-4Rα-/lox小鼠的高敏感性伴随着脾脏、肝脏甚至大脑等外周器官寄生虫负荷的显著增加。dc显示CD11ccreIL-4Rα-/lox小鼠的寄生虫负荷增加，iNOS产生减少。由于DC指令受损，il - 4r α缺失的DC产生IL-12减少，但IL-10增加，IL-23p19和激活素A mRNA表达增加，这些细胞因子先前与促进Th2反应有关。综上所述，这些数据表明，消除dc上的IL-4Rα信号对宿主严重有害，导致疾病快速进展，并且由于杀伤效应功能降低，寄生虫在感染dc中的存活率增加。利什曼病是一种由利什曼原虫原虫引起的寄生虫感染，由白蛉传播。人类的疾病范围从局部皮肤病变到弥散性内脏利什曼病。利什曼原虫大感染小鼠模型表明，C57BL/6小鼠的“愈合”反应需要分泌保护性T辅助（Th） 1细胞因子，包括IFN-γ， IFN-γ通过诱导一氧化氮的产生介导寄生虫的杀伤。相反，“非治愈”BALB/c小鼠无法控制感染并产生以产生IL-4和IL-13细胞因子为特征的Th2免疫应答。虽然IL-4是Th2反应的主要诱导剂，但研究表明，如果在DC激活期间给药，IL-4可以指导树突状细胞（DC）衍生的IL-12的产生和Th1的发育。为了进一步研究DC的作用，我们建立了DC特异性il - 4r α缺失小鼠模型。L.主要研究表明，dc上缺乏IL-4Rα的小鼠外周器官对感染的易感性和寄生虫负荷显著增加。此外，在包括dc在内的宿主细胞中观察到寄生虫负荷增加，其杀伤效应功能减弱。综上所述，本研究表明，il - 4r α介导的dc指令发生在体内，并且是避免宿主疾病快速进展所必需的。
In BALB/c mice, susceptibility to infection with the intracellular parasite Leishmania major is driven largely by the development of T helper 2 (Th2) responses and the production of interleukin (IL)-4 and IL-13, which share a common receptor subunit, the IL-4 receptor alpha chain (IL-4Rα). While IL-4 is the main inducer of Th2 responses, paradoxically, it has been shown that exogenously administered IL-4 can promote dendritic cell (DC) IL-12 production and enhance Th1 development if given early during infection. To further investigate the relevance of biological quantities of IL-4 acting on DCs during in vivo infection, DC specific IL-4Rα deficient (CD11ccreIL-4Rα-/lox) BALB/c mice were generated by gene targeting and site-specific recombination using the cre/loxP system under control of the cd11c locus. DNA, protein, and functional characterization showed abrogated IL-4Rα expression on dendritic cells and alveolar macrophages in CD11ccreIL-4Rα-/lox mice. Following infection with L. major, CD11ccreIL-4Rα-/lox mice became hypersusceptible to disease, presenting earlier and increased footpad swelling, necrosis and parasite burdens, upregulated Th2 cytokine responses and increased type 2 antibody production as well as impaired classical activation of macrophages. Hypersusceptibility in CD11ccreIL-4Rα-/lox mice was accompanied by a striking increase in parasite burdens in peripheral organs such as the spleen, liver, and even the brain. DCs showed increased parasite loads in CD11ccreIL-4Rα-/lox mice and reduced iNOS production. IL-4Rα-deficient DCs produced reduced IL-12 but increased IL-10 due to impaired DC instruction, with increased mRNA expression of IL-23p19 and activin A, cytokines previously implicated in promoting Th2 responses. Together, these data demonstrate that abrogation of IL-4Rα signaling on DCs is severely detrimental to the host, leading to rapid disease progression, and increased survival of parasites in infected DCs due to reduced killing effector functions. Leishmaniasis is a parasitic infection caused by protozoan parasites of Leishmania species and is transmitted by the sandfly. Disease in humans ranges from localized cutaneous lesions to disseminated visceral Leishmaniasis. Mouse models of Leishmania major infection have demonstrated that a “healing” response in C57BL/6 mice requires the secretion of protective T helper (Th) 1 cytokines, including IFN-γ, which mediates parasite killing by inducing nitric oxide production. Conversely, “non-healer” BALB/c mice are unable to control infection and develop a Th2 immune response characterized by the production of IL-4 and IL-13 cytokines. Although IL-4 is the main inducer of Th2 responses, it has been shown that IL-4 can instruct dendritic cell (DC)-derived IL-12 production and Th1 development if administered during DC activation. To further investigate the role of DCs, a DC specific IL-4Rα-deficient mouse model was established. L. major studies demonstrated hypersusceptibility to infection and strikingly increased parasite loads in peripheral organs of mice lacking IL-4Rα on DCs. Moreover, increased parasite burdens were observed in host cells, including DCs, which showed reduced killing effector functions. In summary, this study demonstrates that IL-4Rα-mediated instruction of DCs occurs in vivo and is necessary to avoid rapid progression of disease in the host.
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影响因子：
3.8
作者：
Dewals BG;Marillier RG;Hoving JC;Leeto M;Schwegmann A;Brombacher F
通讯作者：
Brombacher F
重组白介素12治愈感染了利什曼原虫大调的小鼠。
影响因子：
15.3
作者：
Heinzel, F P;Schoenhaut, D S;Rerko, R M;Rosser, L E;Gately, M K
通讯作者：
Gately, M K
影响因子：
56.9
作者：
Diefenbach, A;Schindler, H;Bogdan, C
通讯作者：
Bogdan, C
DOI：
10.1084/jem.20062648
发表时间：
2007-07-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Caton ML;Smith-Raska MR;Reizis B
通讯作者：
Reizis B
影响因子：
56.9
作者：
Guler, ML;Gorham, JD;Murphy, KM
通讯作者：
Murphy, KM