Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
Institute of Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, Germany.
Front Immunol. 2020 Jul 8;11:1397. doi: 10.3389/fimmu.2020.01397. eCollection 2020.
() is a parasite infecting animals and humans. In intermediate hosts, such as humans or rodents, rapidly replicating tachyzoites drive vigorous innate and adaptive immune responses resulting in bradyzoites that survive within tissue cysts. Activation of the innate immune system is critical during the early phase of infection to limit pathogen growth and to instruct parasite-specific adaptive immunity. In rodents, dendritic cells (DCs) sense through TLR11/12, leading to IL-12 production, which activates NK cells to produce IFN-γ as an essential mechanism for early parasite control. Further, C3 can bind to resulting in limited complement activation. Here, we determined the role of C5a/C5aR1 axis activation for the early innate immune response in a mouse model of peritoneal infection. We found that animals suffered from significantly higher weight loss, disease severity, mortality, and parasite burden in the brain than wild type control animals. Severe infection in mice was associated with diminished serum concentrations of IL-12, IL-27, and IFN-γ. Importantly, the serum levels of pro-inflammatory cytokines, including IL-1α, IL-6, and TNF-α, as well as several CXC and CC chemokines, were decreased in comparison to wt animals, whereas anti-inflammatory IL-10 was elevated. The defect in IFN-γ production was associated with diminished mRNA expression in the spleen and the brain, reduced frequency of IFN-γ NK cells in the spleen, and decreased expression in the brain of mice. Mechanistically, DCs from the spleen of mice produced significantly less IL-12 in response to soluble tachyzoite antigen (STAg) stimulation and . Our findings suggest a model in which the C5a/C5aR1 axis promotes IL-12 induction in splenic DCs that is critical for IFN-γ production from NK cells and subsequent iNOS expression in the brain as a critical mechanism to control acute infection.
刚地弓形虫是一种感染动物和人类的寄生虫。在中间宿主（如人类或啮齿动物）中，快速复制的速殖子会引发强烈的先天和适应性免疫反应，导致在组织囊肿中存活的缓殖子。先天免疫系统的激活在感染的早期阶段至关重要，可限制病原体的生长并指导针对寄生虫的适应性免疫。在啮齿动物中，树突状细胞（DC）通过 TLR11/12 感知 ，导致 IL-12 的产生，从而激活 NK 细胞产生 IFN-γ，这是早期控制寄生虫的重要机制。此外，C3 可以与 结合，导致有限的补体激活。在这里，我们确定了 C5a/C5aR1 轴激活在腹膜 感染的小鼠模型中对早期先天免疫反应的作用。我们发现， 感染的动物比野生型对照动物体重减轻、疾病严重程度、死亡率和脑中寄生虫负担显著更高。 感染的严重程度与血清中 IL-12、IL-27 和 IFN-γ浓度降低有关。重要的是，与 wt 动物相比，促炎细胞因子（包括 IL-1α、IL-6 和 TNF-α）和几种 CXC 和 CC 趋化因子的血清水平降低，而抗炎细胞因子 IL-10 升高。IFN-γ 产生缺陷与脾和脑中 mRNA 表达减少、脾中 IFN-γ NK 细胞频率降低以及脑中 表达降低有关。在机制上， 感染的小鼠脾 DC 对可溶性速殖子抗原（STAg）刺激和 的反应中产生的 IL-12 显著减少。我们的研究结果表明，C5a/C5aR1 轴促进脾 DC 中 IL-12 的诱导，这对于 NK 细胞产生 IFN-γ以及随后在脑中表达 iNOS 以作为控制急性 感染的关键机制至关重要。
