Heme-Oxygenase-1 Expression Contributes to the Immunoregulation Induced by Fasciola hepatica and promotes Infection
Heme-Oxygenase-1 Expression Contributes to the Immunoregulation Induced by Fasciola hepatica and promotes Infection
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DOI：
10.3389/fimmu.2017.00883
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发表时间：
2017-07-26
影响因子：
7.3
通讯作者：
Freire, Teresa
中科院分区：
文献类型：
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作者：
Carasi, Paula;Rodriguez, Ernesto;Freire, Teresa
肝片吸虫，又称肝吸虫，是一种感染家畜和人的吸虫，引起肝片吸虫病，由于其在世界范围内的分布和巨大的经济损失，这种人畜共患疾病日益重要。这种寄生虫通过免疫调节树突状细胞(DC)的成熟和巨噬细胞的交替激活来诱导强大的Th2和调节性T免疫反应来调节宿主免疫系统。在这篇文章中，我们证明了小鼠感染肝片吸虫可诱导血红素加氧酶-1(HO-1)的上调，这是调节宿主炎症反应的游离血红素分解代谢中的限速酶。我们展示和表征了两种不同群体的抗原提呈细胞，它们在感染期间在受感染动物的腹膜中表达HO-1。高表达HO-1的细胞表达中等水平的F4/80，但高表达CD11c、CD38、转化生长因子β和IL-10，提示它们对应于调节性DC。另一方面，表达中等水平HO-1的细胞表达高水平的F4/80、CD68、Ly6C和Fizz-1，表明它们可能对应于交替激活的巨噬细胞。此外，合成的金属卟啉铜对HO-1的药理诱导促进了肝片吸虫的感染，增加了与该病相关的临床症状。相反，用HO-1抑制剂SnPP治疗可以保护小鼠免受寄生虫感染，这表明HO-1在肝片吸虫感染过程中发挥了重要作用。最后，HO-1在肝片吸虫感染过程中的表达与肝脏和腹膜中的转化生长因子β和IL-10水平相关，提示HO-1在感染过程中控制这些免疫调节细胞因子的表达，有利于寄生虫在宿主中的存活。这些结果有助于阐明肝片吸虫在宿主体内诱导的免疫调节机制，并为控制肝片吸虫病提供替代检查点。
Fasciola hepatica, also known as the liver fluke, is a trematode that infects livestock and humans causing fasciolosis, a zoonotic disease of increasing importance due to its worldwide distribution and high economic losses. This parasite immunoregulates the host immune system by inducing a strong Th2 and regulatory T immune response by immunomodulating dendritic cell (DC) maturation and alternative activation of macrophages. In this paper, we show that F. hepatica infection in mice induces the upregulation of heme-oxygenase-1 (HO-1), the rate-limiting enzyme in the catabolism of free heme that regulates the host inflammatory response. We show and characterize two different populations of antigen presenting cells that express HO-1 during infection in the peritoneum of infected animals. Cells that expressed high levels of HO-1 expressed intermediate levels of F4/80 but high expression of CD11c, CD38, TGF beta, and IL-10 suggesting that they correspond to regulatory DCs. On the other hand, cells expressing intermediate levels of HO-1 expressed high levels of F4/80, CD68, Ly6C, and FIZZ-1, indicating that they might correspond to alternatively activated macrophages. Furthermore, the pharmacological induction of HO-1 with the synthetic metalloporphyrin CoPP promoted F. hepatica infection increasing the clinical signs associated with the disease. In contrast, treatment with the HO-1 inhibitor SnPP protected mice from parasite infection, indicating that HO-1 plays an essential role during F. hepatica infection. Finally, HO-1 expression during F. hepatica infection was associated with TGF beta and IL-10 levels in liver and peritoneum, suggesting that HO-1 controls the expression of these immunoregulatory cytokines during infection favoring parasite survival in the host. These results contribute to the elucidation of the immunoregulatory mechanisms induced by F. hepatica in the host and provide alternative checkpoints to control fasciolosis.