Deficiency in astrocyte CCL2 production reduces neuroimmune control of Toxoplasma gondii infection.
Deficiency in astrocyte CCL2 production reduces neuroimmune control of Toxoplasma gondii infection.
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DOI：
10.1371/journal.ppat.1011710
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发表时间：
2024-01
期刊：
影响因子：
6.7
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中科院分区：
文献类型：
--
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弓形虫是一种专性的细胞内寄生虫，感染了世界三分之一的人口，并在大脑中建立了感染。大脑免疫细胞的渗透对控制寄生虫至关重要，但人们对感染期间引导免疫细胞进入大脑的分子线索知之甚少。激活的星形胶质细胞产生CCL2，这是一种趋化因子，通过与CCR2受体结合，介导炎性单核细胞向组织募集。在弓形虫感染后15天，我们检测到C57BL/6J小鼠大脑中CCL2的产生增加。利用共聚焦显微镜和细胞内流式细胞术，我们确定小胶质细胞和脑浸润性髓样细胞是急性感染期间产生CCL2的主要细胞，并且CCL2是在脑寄生虫感染的区域特异性产生的。相反，在弓形虫慢性感染期间，星形胶质细胞成为主要的CCL2产生细胞。为了确定星形胶质细胞来源的CCL2在动员免疫细胞到大脑和控制弓形虫感染方面的作用，我们建立了GFAP-CRE x CCL2fl/fl小鼠，其中星形胶质细胞缺乏CCL2产生。我们观察到，在星形胶质细胞CCL2产生缺陷的小鼠慢性(非急性)感染期间，免疫细胞募集显著减少，脑内寄生虫负担增加，而对外周免疫反应没有影响。为了探讨弓形虫感染控制减弱的可能机制，我们分析了弓形虫宿主防御中的关键抗菌素和免疫角色，并在敲除小鼠中检测到iNOS+髓系细胞和弓形虫特异性CD4+T细胞减少。这些数据揭示了星形胶质细胞来源的CCL2在慢性但非急性弓形虫感染期间大脑中免疫细胞招募和寄生虫控制中的关键作用。神经炎症在保护大脑免受感染方面发挥着重要作用，但必须加以控制，以防止对大脑的损害。弓形虫是一种专性细胞内食源性寄生虫，感染了世界三分之一的人口。在病原体中，弓形虫具有罕见的穿越血脑屏障并在大脑中建立慢性感染的能力，从而诱导保护性但非灭菌的免疫反应。在这项研究中，我们检测了弓形虫感染小鼠，以了解驱动脑部感染的神经炎性反应的因素。我们确定了产生强大趋化因子CCL2的细胞在感染过程中发生了变化：在急性感染期间，髓系细胞是主要的CCL2产生细胞，而在慢性感染期间，星形胶质细胞成为主要的CCL2产生细胞。此外，切除星形胶质细胞特异性产生的CCL2减少了免疫细胞向大脑的募集，并降低了慢性感染期间对寄生虫的控制。因此，星形胶质细胞来源的CCL2在控制慢性但不是急性的弓形虫感染方面起着关键作用。
Toxoplasma gondii is an obligate intracellular parasite that infects one-third of the world’s human population and establishes infection in the brain. Cerebral immune cell infiltration is critical for controlling the parasite, but little is known about the molecular cues guiding immune cells to the brain during infection. Activated astrocytes produce CCL2, a chemokine that mediates inflammatory monocyte recruitment to tissues by binding to the CCR2 receptor. We detected elevated CCL2 production in the brains of C57BL/6J mice by 15 days after T. gondii infection. Utilizing confocal microscopy and intracellular flow cytometry, we identified microglia and brain-infiltrating myeloid cells as the main producers of CCL2 during acute infection, and CCL2 was specifically produced in regions of parasite infection in the brain. In contrast, astrocytes became the dominant CCL2 producer during chronic T. gondii infection. To determine the role of astrocyte-derived CCL2 in mobilizing immune cells to the brain and controlling T. gondii infection, we generated GFAP-Cre x CCL2fl/fl mice, in which astrocytes are deficient in CCL2 production. We observed significantly decreased immune cell recruitment and increased parasite burden in the brain during chronic, but not acute, infection of mice deficient in astrocyte CCL2 production, without an effect on peripheral immune responses. To investigate potential mechanisms explaining the reduced control of T. gondii infection, we analyzed key antimicrobial and immune players in host defense against T. gondii and detected a reduction in iNOS+ myeloid cells, and T. gondii-specific CD4+ T cells in the knockout mice. These data uncover a critical role for astrocyte-derived CCL2 in immune cell recruitment and parasite control in the brain during chronic, but not acute, T. gondii infection. Neuroinflammation plays an important role in protecting the brain against infection, but it must be controlled to prevent damage to the brain. Toxoplasma gondii is an obligate intracellular foodborne parasite that infects one-third of the world’s human population. Among pathogens, T. gondii has the rare ability to cross the blood-brain barrier and establish chronic infection in the brain, inducing a protective, but non-sterilizing immune response. In this study, we examined T. gondii infection of mice to understand the factors driving the neuroinflammatory response to infection of the brain. We determined that the cells producing the potent chemokine, CCL2, changed over the course of infection: myeloid cells were the main CCL2 producers during acute infection, whereas astrocytes became the dominant CCL2 producers during chronic infection. Additionally, the ablation of CCL2 production specifically from astrocytes reduced immune cell recruitment to the brain and decreased control of the parasite during chronic infection. Therefore, astrocyte-derived CCL2 plays a critical role in the control of chronic, but not acute, T. gondii infection.
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