VISTA regulates microglia homeostasis and myelin phagocytosis, and is associated with MS lesion pathology

Acta Neuropathologica Communications

Malte Borggrewe¹  Bart J. L. Eggen¹  Maaike L. Brummer¹  Evelyn M. Wesseling¹  Fenja L. Gierschek¹  Susanne M. Kooistra¹  Jon D. Laman¹  Tegan A. Otto¹  Tiago Medeiros-Furquim¹  Randolph J. Noelle²  Elizabeth C. Nowak²  Sam W. Lee³ 

[1] Department of Biomedical Sciences of Cells and Systems, Section Molecular Neurobiology, University Medical Center Groningen, University of Groningen, and MS Centrum Noord Nederland (MSCNN), Groningen, The Netherlands;Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, NH, USA;Yale University School of Medicine, New Haven, CT, USA;

关键词: Immunotherapy;    Neurodegeneration;    Glial cells;    Demyelination;    PD-1H;    Checkpoint inhibition;   

DOI  :  10.1186/s40478-021-01186-7

来源: Springer

【 摘 要 】

V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) is a negative checkpoint regulator (NCR) that is involved in T-cell quiescence, inhibition of T-cell activation, and in myeloid cells regulates cytokine production, chemotaxis, phagocytosis, and tolerance induction. In the central nervous system (CNS), VISTA is expressed by microglia, the resident macrophage of the parenchyma, and expression is decreased during neuroinflammation; however, the function of VISTA in microglia is unknown. Here, we extensively analyzed VISTA expression in different MS lesion stages and characterized the function of VISTA in the CNS by deleting VISTA in microglia. VISTA is differentially expressed in distinct MS lesion stages. In mice, VISTA deletion in Cx3Cr1-expressing cells induced a more amoeboid microglia morphology, indicating an immune-activated phenotype. Expression of genes associated with cell cycle and immune-activation was increased in VISTA KO microglia. In response to LPS and during experimental autoimmune encephalomyelitis (EAE), VISTA KO and WT microglia shared similar transcriptional profiles and VISTA deletion did not affect EAE disease progression or microglia responses. VISTA KO in microglia in vitro decreased the uptake of myelin. This study demonstrates that VISTA is involved in microglia function, which likely affects healthy CNS homeostasis and neuroinflammation.

【 授权许可】

CC BY