CCR2 Signaling Promotes Brain Infiltration of Inflammatory Monocytes and Contributes to Neuropathology during Cryptococcal Meningoencephalitis.
CCR2 Signaling Promotes Brain Infiltration of Inflammatory Monocytes and Contributes to Neuropathology during Cryptococcal Meningoencephalitis.
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DOI：
10.1128/mbio.01076-21
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发表时间：
2021-08-31
期刊：
影响因子：
6.4
通讯作者：
Olszewski MA
中科院分区：
文献类型：
--
作者：
Xu J;Ganguly A;Zhao J;Ivey M;Lopez R;Osterholzer JJ;Cho CS;Olszewski MA
隐球菌性脑膜脑炎（CM）是世界范围内中枢神经系统（CNS）感染相关死亡的主要原因，存活的患者通常会出现神经系统缺陷。虽然CNS炎症与CM的发病机制有关，但关于特定炎症/免疫途径对CNS病理学与真菌清除的相对贡献知之甚少。脑脊液C-C趋化因子受体2（CCR 2）配体CCL 2水平升高与CM患者疾病恶化相关使用小鼠模型，我们研究了CCR 2通路在CM期间CNS炎症和病理学发展中的作用。我们发现，CCR 2缺陷小鼠表现出改善的28天存活率和减轻神经系统疾病评分，尽管脑真菌负荷高于WT小鼠。CCR 2缺陷小鼠中CM病理学的减少伴随着隐球菌微囊周围神经元细胞死亡的显著减少，并恢复了参与脑中神经传递、连接和神经元细胞结构的基因的表达。结果表明，CCR 2轴是将CD 45 hiCD 11b + Ly 6C+炎性单核细胞募集到脑的主要途径，并间接调节CD 4 + T细胞和CD 8 + T细胞的积聚。特别地，CCR 2轴促进产生干扰素γ（IFN-γ）的CD 4 + T细胞的募集和骨髓细胞的经典活化。在这种情况下，CCR 2缺失限制了我们在CM中看到的免疫网络失调，并减轻了神经病理学。因此，CCR 2轴是旨在限制CM患者中炎性CNS病理学的干预的潜在靶点。
Cryptococcal meningoencephalitis (CM) is a leading cause of central nervous system (CNS) infection-related mortality worldwide, with surviving patients often developing neurological deficiencies. While CNS inflammation has been implicated in the pathogenesis of CM, little is known about the relative contribution of the specific inflammatory/immune pathways to CNS pathology versus fungal clearance. Increased cerebrospinal fluid level of C-C chemokine receptor 2 (CCR2) ligand CCL2 is associated with disease deterioration in patients with CM. Using a murine model, we investigated the role of the CCR2 pathway in the development of CNS inflammation and pathology during CM. We found that CCR2-deficient mice exhibited improved 28-day survival and alleviated neurological disease scores despite a brain fungal burden higher than that of the WT mice. Reduced CM pathology in CCR2-deficient mice was accompanied by markedly decreased neuronal cell death around cryptococcal microcysts and restored expression of genes involved in neurotransmission, connectivity, and neuronal cell structure in the brains. Results show that CCR2 axis is the major pathway recruiting CD45hiCD11b+Ly6C+ inflammatory monocyte to the brain and indirectly modulates the accumulation of CD4+ T cells and CD8+ T cells. In particular, CCR2 axis promotes recruitment of interferon gamma (IFN-γ)-producing CD4+ T cells and classical activation of myeloid cells. In this context, CCR2 deletion limits the immune network dysregulation we see in CM and attenuates neuropathology. Thus, the CCR2 axis is a potential target for interventions aimed to limit inflammatory CNS pathology in CM patients.