Clonal hematopoiesis in monocytes contributes to HIV-associated neuroinflammation

单核细胞的克隆造血作用导致 HIV 相关的神经炎症

• 批准号: 10534823
• 负责人: SANJAY B. MAGGIRWAR
• 金额: $ 47.26万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10534823
• 关键词: 3-Dimensional; Adhesions; Affect; Anti-HIV Agents; Antibodies; Blood - brain barrier anatomy; Blood Circulation; Blood Platelets; Blood Vessels; Brain; Brain Diseases; Cell Adhesion Molecules; Cell Differentiation process; Cells; Characteristics; Chronic; Clonal Expansion; DNA Methylation; DNA Modification Methylases; Data; Dioxygenases; Endothelium; Epigenetic Process; Event; Exhibits; Exposure to; Extravasation; Functional disorder; Gene Expression; General Population; Genes; Goals; HIV; HIV Infections; HIV Seronegativity; HIV Seropositivity; HIV-1; Hematopoiesis; Heterogeneity; Human; Immune; Impaired cognition; Individual; Infiltration; Inflammatory; Injury; Integrins; Intercellular adhesion molecule 1; JAK2 gene; Learning; Literature; Measures; Mediating; Modeling; Monoclonal Antibodies; Mus; Myeloid Cells; Nervous System Trauma; Neuraxis; Neurologic; Neurologic Symptoms; Neuronal Dysfunction; P-Selectin; P-selectin ligand protein; Phenotype; Physiological; Play; Process; Promoter Regions; Proto-Oncogene Proteins c-myc; Role; Secondary to; Site; Testing; Tetanus Helper Peptide; Time; Vascular Cell Adhesion Molecule-1; Wild Type Mouse; antiretroviral therapy; astrogliosis; axon injury; base; brain endothelial cell; cognitive ability; demethylation; experimental study; gene product; improved; macrophage; migration; monocyte; monolayer; mouse model; neuroinflammation; neuroregulation; novel; promoter; response; shear stress

Summary Extravasation of inflammatory monocytes across the blood-brain barrier (BBB) in response to human immunodeficiency virus type-1 (HIV) is a critical event that leads to chronic neuroinflammation, neurologic injury, and subsequent loss of cognitive abilities in a significantly large number of infected individuals. However, given the heterogeneity of monocytes that exists in HIV-infected individuals receiving anti-retroviral therapy (ART), it remains unknown as to whether the neuro-modulatory actions of monocytes are limited to select subset of monocytes. Directly relevant to the goals of RFA-21-250, our supporting data reveals that the ART-treated HIV- infected individuals harbor higher numbers of inflammatory monocytes (CD14lowCD16hi) in their circulation. These cells also exhibit characteristic features of clonal hematopoiesis (CH), such as loss of DNA methyltransferase 3A (DNMT3A) and Tet methylcytosine dioxygenase 2 (TET2) with concurrent increase in the expression of janus kinase-2 (Jak2 ; these three gene products, and few others, are often termed as CH drivers). Interestingly, subsequent experiments in various models suggested that this monocyte subset (1) translocate to the central nervous system (CNS) in response to ART, in platelet-dependent manner, (2) is neuro-modulatory in action, and (3) can be expanded following exposure of monocytes to activated platelets and ART. Based on these findings, we posit that the priming of monocytes by activated platelets potentiates ART-mediated clonal hematopoiesis in monocytes, leading to HIV-associated neurologic injury. In this model, we propose that the composite effect of activated platelets and ART results into clonal expansion of inflammatory (CD14lowCD16hi) monocyte subset with CH, and subsequent demethylation/induction of PSGL-1 gene in them. Functionally, these events facilitate the transmigration of such monocytes into the perivascular spaces within the CNS, where these cells differentiate into macrophage phenotype, while retaining CH profile, and contribute to the neuronal dysfunction. This model then, in full accordance with the available literature, accounts for how neurologic manifestations are initiated and maintained due to immune-CNS interaction in ART-treated HIV- infected individuals.

总结 炎症性单核细胞对人血脑屏障（BBB）的反应 1型免疫缺陷病毒（HIV）是导致慢性神经炎症，神经损伤， 以及随后大量感染个体的认知能力丧失。但鉴于 接受抗逆转录病毒治疗（ART）的HIV感染者中存在的单核细胞异质性， 目前尚不清楚单核细胞的神经调节作用是否仅限于选择的 单核细胞与RFA-21-250的目标直接相关，我们的支持性数据显示，ART治疗的HIV- 感染的个体在其循环中具有较高数量的炎性单核细胞（CD 14低CD 16高）。 这些细胞还表现出克隆造血（CH）的特征，如DNA丢失 甲基转移酶3A（DNMT 3A）和泰特甲基胞嘧啶双加氧酶2（TET 2），同时增加 janus激酶-2（Jak 2;这三种基因产物和少数其他基因产物通常被称为CH驱动器）的表达。 有趣的是，随后在各种模型中的实验表明，这种单核细胞亚群（1）易位到 中枢神经系统（CNS）以血小板依赖性方式对ART作出反应，（2）在以下方面具有神经调节作用： 作用，和（3）在单核细胞暴露于活化的血小板和ART后可以扩增。 通过这些发现，我们认为活化的血小板对单核细胞的刺激增强了ART介导的 单核细胞的克隆造血，导致HIV相关的神经损伤。在这个模型中，我们建议 活化血小板和ART的复合作用导致炎症细胞的克隆性扩增， （CD 14 lowCD 16 hi）单核细胞亚群，随后在其中进行PSGL-1基因的去甲基化/诱导。 从功能上讲，这些事件促进了此类单核细胞迁移到血管周间隙中。 CNS，其中这些细胞分化成巨噬细胞表型，同时保留CH特征，并有助于 神经元功能障碍然后，这个模型与现有文献完全一致，说明了 在ART治疗的HIV中，由于免疫-CNS相互作用，神经系统表现开始并维持， 感染的人。