Quirino Gustavo F S, Nascimento Manuela S L, Davoli-Ferreira Marcela, Sacramento Lais A, Lima Mikhael H F, Almeida Roque P, Carregaro Vanessa, Silva João Santana
Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
Biological and Health Science Center, Federal University of Sergipe, Aracaju, SE, Brazil.
Infect Immun. 2016 Jul 21;84(8):2289-2298. doi: 10.1128/IAI.00283-16. Print 2016 Aug.
The relationship established between Leishmania infantum and the vertebrate host can lead to a self-healing infection or to the manifestation of visceral leishmaniasis, a chronic systemic infection associated with high rates of mortality. We hypothesized that regulatory cytokines, such as interleukin-27 (IL-27), play a role in susceptibility to L. infantum infection. IL-27 is a heterodimeric cytokine composed of IL-27p28 and EBi3 subunits which, when combined, bind to IL-27R, leading to STAT-1 and -3 activation, playing a role in the regulation of the immune response. We observed in this work that IL-27 regulates the Th1/Th17 profiles in a mouse model of visceral leishmaniasis (VL) caused by L. infantum We showed here that the pathogen recognition by endosomal Toll-like receptors triggers a type I interferon (IFN) response, which acts through the type I IFN receptor and interferon regulatory factor 1 to induce IL-27 production by macrophages. Furthermore, IL-27 plays a major regulatory role in vivo, because Ebi3(-/-) mice can efficiently control parasite replication despite reduced levels of IFN-γ compared to wild-type mice. On the other hand, the absence of Ebi3 leads to exacerbated IL-17A production in the infected organs as well as in a coculture system, suggesting a direct regulatory action of IL-27 during L. infantum infection. As a consequence of exacerbated IL-17A in Ebi3(-/-) mice, a greater neutrophil influx was observed in the target organs, playing a role in parasite control. Thus, this work unveiled the molecular steps of IL-27 production after L. infantum infection and demonstrated its regulatory role in the IL-17A-neutrophil axis.
婴儿利什曼原虫与脊椎动物宿主之间建立的关系可导致自愈性感染或内脏利什曼病的表现，内脏利什曼病是一种与高死亡率相关的慢性全身感染。我们假设调节性细胞因子，如白细胞介素-27（IL-27），在婴儿利什曼原虫感染易感性中起作用。IL-27是一种由IL-27p28和EBi3亚基组成的异二聚体细胞因子，二者结合后与IL-27R结合，导致STAT-1和STAT-3激活，在免疫反应调节中发挥作用。我们在这项研究中观察到，IL-27在内脏利什曼病（VL）小鼠模型中调节Th1/Th17细胞谱，该模型由婴儿利什曼原虫引起。我们在此表明，内体Toll样受体对病原体的识别触发I型干扰素（IFN）反应，该反应通过I型IFN受体和干扰素调节因子1起作用，诱导巨噬细胞产生IL-27。此外，IL-27在体内起主要调节作用，因为与野生型小鼠相比，Ebi3基因敲除小鼠尽管IFN-γ水平降低，但仍能有效控制寄生虫复制。另一方面，Ebi3的缺失导致感染器官以及共培养系统中IL-17A产生加剧，表明IL-27在婴儿利什曼原虫感染期间具有直接调节作用。由于Ebi3基因敲除小鼠中IL-17A加剧，在靶器官中观察到更多的中性粒细胞流入，这在寄生虫控制中发挥作用。因此，这项研究揭示了婴儿利什曼原虫感染后IL-27产生的分子步骤，并证明了其在IL-17A-中性粒细胞轴中的调节作用。
