Browsing by Author "Lopez, Jacqueline A."

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    CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10
    (Cell Press, 2020) Guldner, Ian H.; Wang, Qingfei; Yang, Lin; Golomb, Samantha M.; Zhao, Zhuo; Lopez, Jacqueline A.; Brunory, Abigail; Howe, Erin N.; Zhang, Yizhe; Palakurthi, Bhavana; Barron, Martin; Gao, Hongyu; Xuei, Xiaoling; Liu, Yunlong; Li, Jun; Chen, Danny Z.; Landreth, Gary E.; Zhang, Siyuan; Medical and Molecular Genetics, School of Medicine
    Brain metastasis (br-met) develops in an immunologically unique br-met niche. Central nervous system-native myeloid cells (CNS-myeloids) and bone-marrow-derived myeloid cells (BMDMs) cooperatively regulate brain immunity. The phenotypic heterogeneity and specific roles of these myeloid subsets in shaping the br-met niche to regulate br-met outgrowth have not been fully revealed. Applying multimodal single-cell analyses, we elucidated a heterogeneous but spatially defined CNS-myeloid response during br-met outgrowth. We found Ccr2+ BMDMs minimally influenced br-met while CNS-myeloid promoted br-met outgrowth. Additionally, br-met-associated CNS-myeloid exhibited downregulation of Cx3cr1. Cx3cr1 knockout in CNS-myeloid increased br-met incidence, leading to an enriched interferon response signature and Cxcl10 upregulation. Significantly, neutralization of Cxcl10 reduced br-met, while rCxcl10 increased br-met and recruited VISTAHi PD-L1+ CNS-myeloid to br-met lesions. Inhibiting VISTA- and PD-L1-signaling relieved immune suppression and reduced br-met burden. Our results demonstrate that loss of Cx3cr1 in CNS-myeloid triggers a Cxcl10-mediated vicious cycle, cultivating a br-met-promoting, immune-suppressive niche.
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    Multi-modal Single-Cell Analysis Reveals Brain Immune Landscape Plasticity during Aging and Gut Microbiota Dysbiosis
    (Elsevier, 2020-12-01) Golomb, Samantha M.; Guldner, Ian H.; Zhao, Anqi; Wang, Qingfei; Palakurthi, Bhavana; Aleksandrovic, Emilija A.; Lopez, Jacqueline A.; Lee, Shaun W.; Yang, Kai; Zhang, Siyuan; Medicine, School of Medicine
    Phenotypic and functional plasticity of brain immune cells contribute to brain tissue homeostasis and disease. Immune cell plasticity is profoundly influenced by tissue microenvironment cues and systemic factors. Aging and gut microbiota dysbiosis that reshape brain immune cell plasticity and homeostasis has not been fully delineated. Using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq), we analyze compositional and transcriptional changes of the brain immune landscape in response to aging and gut dysbiosis. Discordance between canonical surface-marker-defined immune cell types and their transcriptomes suggest transcriptional plasticity among immune cells. Ly6C+ monocytes predominate a pro-inflammatory signature in the aged brain, while innate lymphoid cells (ILCs) shift toward an ILC2-like profile. Aging increases ILC-like cells expressing a T memory stemness (Tscm) signature, which is reduced through antibiotics-induced gut dysbiosis. Systemic changes due to aging and gut dysbiosis increase propensity for neuroinflammation, providing insights into gut dysbiosis in age-related neurological diseases.