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首页> 外文期刊>MBio >The IL-33/ST2 Axis Is Associated with Human Visceral Leishmaniasis and Suppresses Th1 Responses in the Livers of BALB/c Mice Infected with Leishmania donovani
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The IL-33/ST2 Axis Is Associated with Human Visceral Leishmaniasis and Suppresses Th1 Responses in the Livers of BALB/c Mice Infected with Leishmania donovani

机译：IL-33 / ST2轴与人类内脏利什曼病相关，并抑制感染了利什曼原虫的BALB / c小鼠肝脏中的Th1反应。

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During visceral leishmaniasis, the control of hepatic parasite burden is mainly due to granuloma assembly in a microenvironment consisting of both Th1 and Th2 components. Using enzyme-linked immunosorbent assay (ELISA) dosages, quantitative PCR (qPCR), immunohistochemistry, and flow cytometry, we studied the role of interleukin-33 (IL-33), a recently described cytokine signaling through the ST2 receptor, during visceral leishmaniasis. We showed that a higher level of IL-33 was detected in the serum of patients with visceral leishmaniasis than in that from healthy donors and demonstrated the presence of IL-33+ cells in a liver biopsy specimen from a patient. Similarly, in BALB/c mice experimentally infected with L.?donovani, a higher level of IL-33 was detected in the serum, as well as the presence of IL-33+ cells and ST2+ cells in the mouse liver. In ST2?/? BALB/c mice, better control of the hepatic parasite burden and reduced hepatomegaly were observed. This was associated with strong induction of Th1 cytokines (gamma interferon [IFN-γ] and IL-12) compared to the level in wild-type (WT) mice and better recruitment of myeloid cells associated with strongly induced chemokines (CCL2 and CXCL2) and receptors (CCR2 and CXCR2). Conversely, BALB/c mice treated twice weekly with recombinant IL-33 showed a dramatically reduced induction of Th1 cytokines and delayed inhibition of monocyte and neutrophil recruitment in the liver, which was associated with reduced KC/CXCL1 and CXCR2 expression. Taken together, our results suggest that IL-33 could be a new deleterious regulator of the hepatic immune response against Leishmania donovani, via the repression of the Th1 response and myeloid cell recruitment. >IMPORTANCE Visceral leishmaniasis is a life-threatening systemic disease due to the Leishmania protozoa L.?infantum and L.?donovani and is ranked by the World Health Organization as the second most important protozoan parasitic disease after malaria for its grave morbidity, high mortality, and global distribution. Leishmania parasites subvert the host’s immune response to propagate to target organs, including the spleen, the bone marrow, and the liver. Control of hepatic parasite burdens depends on a delicate and poorly understood Th1/Th2 immune balance. To better understand this complex immune response, new cytokines are interesting targets for research studies. IL-33 is a newly described cytokine usually associated with Th2 response and involved in different diseases, including infectious diseases and hepatitis. Our results suggest that IL-33 could be a new factor of susceptibility and a potential prognostic marker during visceral leishmaniasis.
机译：内脏利什曼病期间，肝寄生虫负担的控制主要是由于肉芽肿在由Th1和Th2组成的微环境中聚集。使用酶联免疫吸附测定（ELISA）剂量，定量PCR（qPCR），免疫组化和流式细胞仪，我们研究了白介素33（IL-33）（最近描述的通过ST2受体通过内脏利什曼病发生的细胞因子信号传导）的作用。 。我们显示，内脏利什曼病患者血清中检测到的IL-33水平高于健康供体患者，并证明了肝脏活检标本中存在IL-33 + 细胞。患者。类似地，在实验感染了 donovani 的BALB / c小鼠中，血清中检测到更高水平的IL-33，并且存在IL-33 + 细胞和ST2 + 细胞。在ST2 ？/？ BALB / c小鼠中，观察到更好地控制了肝寄生虫负担并减少了肝肿大。与野生型（WT）小鼠的水平相比，这与Th1细胞因子（γ干扰素[IFN-γ]和IL-12）的强诱导作用以及与强诱导趋化因子（CCL2和CXCL2）相关的髓样细胞的募集更好有关和受体（CCR2和CXCR2）。相反，每周用重组IL-33处理两次的BALB / c小鼠显示Th1细胞因子的诱导显着降低，并且延迟了单核细胞和中性粒细胞募集在肝脏中的抑制，这与KC / CXCL1和CXCR2表达降低有关。两者合计，我们的结果表明，IL-33可能通过抑制Th1反应和募集骨髓细胞而成为针对 Leishmania donovani 的肝免疫反应的新有害调节剂。 >重要性：内脏利什曼病是一种威胁生命的全身性疾病，归因于 Leishmania 原生动物 L.?infantum 和 L.?donovani ，由于其严重的发病率，高的死亡率和全球分布，被世界卫生组织列为仅次于疟疾的第二重要的原生动物寄生虫病。 利什曼原虫病寄生虫破坏了宿主的免疫反应，从而传播到目标器官，包括脾脏，骨髓和肝脏。肝寄生虫负担的控制取决于脆弱的，尚不了解的Th1 / Th2免疫平衡。为了更好地理解这种复杂的免疫反应，新的细胞因子是研究的有趣目标。 IL-33是一种新近描述的细胞因子，通常与Th2反应相关，并涉及多种疾病，包括传染病和肝炎。我们的结果表明，IL-33可能是内脏利什曼病期间的新敏感性因素和潜在的预后标志物。

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