作者
Iain C. Clark,Cristina Gutiérrez-Vázquez,Michael A. Wheeler,Zhaorong Li,Veit Rothhammer,Mathias Linnerbauer,Liliana M. Sanmarco,Lankai Guo,Manon Blain,Stéphanie Zandee,Chun‐Cheih Chao,Katelyn V. Batterman,Marius Schwabenland,Peter Lotfy,Amalia Tejeda Velarde,Patrick Hewson,Carolina Manganeli Polonio,Michael W. Shultis,Yasmin Salem,Emily Tjon,Pedro Henrique Fonseca-Castro,Davis Borucki,Kalil Alves de Lima,Agustín Plasencia,Douglas L. Rosene,Kevin J. Hodgetts,Marco Prinz,Jack Antel,Alexandre Prat,Francisco J. Quintana
摘要
Cell-cell interactions control the physiology and pathology of the central nervous system (CNS). To study astrocyte cell interactions in vivo, we developed rabies barcode interaction detection followed by sequencing (RABID-seq), which combines barcoded viral tracing and single-cell RNA sequencing (scRNA-seq). Using RABID-seq, we identified axon guidance molecules as candidate mediators of microglia-astrocyte interactions that promote CNS pathology in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis (MS). In vivo cell-specific genetic perturbation EAE studies, in vitro systems, and the analysis of MS scRNA-seq datasets and CNS tissue established that Sema4D and Ephrin-B3 expressed in microglia control astrocyte responses via PlexinB2 and EphB3, respectively. Furthermore, a CNS-penetrant EphB3 inhibitor suppressed astrocyte and microglia proinflammatory responses and ameliorated EAE. In summary, RABID-seq identified microglia-astrocyte interactions and candidate therapeutic targets.