Ly6Chigh Monocytes Control Cerebral Toxoplasmosis
Ly6Chigh Monocytes Control Cerebral Toxoplasmosis
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DOI：
10.4049/jimmunol.1402037
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发表时间：
2015-04-01
影响因子：
4.4
通讯作者：
Dunay, Ildiko Rita
中科院分区：
文献类型：
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作者：
Biswas, Aindrila;Bruder, Dunja;Dunay, Ildiko Rita
寄生虫弓形虫的脑感染之后是驻留细胞的激活和免疫细胞从外周向CNS的募集。在这项研究中，我们发现一个髓系细胞亚群，即Ly 6C（高）CCR 2（+）炎性单核细胞，在慢性T细胞增多时浸润大脑。弓形虫感染，在宿主防御中起着决定性的作用。这种单核细胞亚群的消耗导致寄生虫负荷升高和感染小鼠的存活率降低，表明它们的关键作用。值得注意的是，Ly 6C（高）CCR 2（+）单核细胞由于产生促炎介质如IL-1 α、IL-1 β、IL-6、诱导型NO合酶、TNF和活性氧中间体而控制寄生虫控制。有趣的是，Ly 6C（高）CCR 2（+）单核细胞也能够产生调节细胞因子IL-10，揭示了它们的双重特征。此外，我们通过过继转移证实，募集的单核细胞进一步发育成两个不同的亚群，有助于寄生虫控制和深刻的宿主防御。分化的Ly 6C（int）CCR（2）+F4/80（int）亚群上调MHC I和MHC II分子，表明树突状细胞的特性，如与T细胞的相互作用，而Ly 6C（neg）F4/80（high）细胞亚群显示出升高的吞噬能力，同时上调髓样细胞-2上表达的触发受体。最后，我们已经表明，招募Ly 6C（高）单核细胞的中枢神经系统是由P-选择素糖蛋白配体-1。这些结果表明，招募的Ly 6C（高）单核细胞对脑弓形虫病的至关重要性，并揭示了进一步分化的骨髓来源的单核细胞亚群在寄生虫控制和免疫调节中枢神经系统的行为。
Cerebral infection with the parasite Toxoplasma gondii is followed by activation of resident cells and recruitment of immune cells from the periphery to the CNS. In this study, we show that a subset of myeloid cells, namely Ly6C(high)CCR2(+) inflammatory monocytes that infiltrate the brain upon chronic T. gondii infection, plays a decisive role in host defense. Depletion of this monocyte subset resulted in elevated parasite load and decreased survival of infected mice, suggesting their crucial role. Notably, Ly6C(high)CCR2(+) monocytes governed parasite control due to production of proinflammatory mediators, such as IL-1 alpha, IL-1 beta, IL-6, inducible NO synthase, TNF, and reactive oxygen intermediate. Interestingly, Ly6C(high)CCR2(+) monocytes were also able to produce the regulatory cytokine IL-10, revealing their dual feature. Moreover, we confirmed by adoptive transfer that the recruited monocytes further develop into two distinct subpopulations contributing to parasite control and profound host defense. The differentiated Ly6C(int)CCR(2)+F4/80(int) subset upregulated MHC I and MHC II molecules, suggesting dendritic cell properties such as interaction with T cells, whereas the Ly6C(neg)F4/80(high) cell subset displayed elevated phagocytic capacity while upregulating triggering receptor expressed on myeloid cells-2. Finally, we have shown that the recruitment of Ly6C(high) monocytes to the CNS is regulated by P-selectin glycoprotein ligand-1. These results indicate the critical importance of recruited Ly6C(high) monocytes upon cerebral toxoplasmosis and reveal the behavior of further differentiated myeloid-derived mononuclear cell subsets in parasite control and immune regulation of the CNS.