VISTA expression by microglia decreases during inflammation and is differentially regulated in CNS diseases

被引:75
作者
Borggrewe, Malte [1 ]
Grit, Corien [1 ]
Den Dunnen, Wilfred F. A. [2 ]
Burm, Saskia M. [3 ,5 ]
Bajramovic, Jeffrey J. [3 ]
Noelle, Randolph J. [4 ]
Eggen, Bart J. L. [1 ]
Laman, Jon D. [1 ]
机构
[1] Univ Groningen, Univ Med Ctr Groningen, Sect Med Physiol, Dept Neurosci, A Deusinglaan 1, NL-9713 AV Groningen, Netherlands
[2] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol, Groningen, Netherlands
[3] Biomed Primate Res Ctr, Alternat Unit, Rijswijk, Netherlands
[4] Geisel Sch Med Dartmouth, Norris Cotton Canc Ctr, Dept Microbiol & Immunol, Lebanon, NH USA
[5] Genmab BV, Uppsalalaan 15, NL-3584 CT Utrecht, Netherlands
关键词
autoimmunity; cancer; DD1alpha; immune checkpoints; immunotherapy; neurodegeneration; PD-1H; IMMUNE-CHECKPOINT BLOCKADE; MULTIPLE-SCLEROSIS; AMYLOID-BETA; CELLS; MOUSE; PATHWAY; ACTIVATION; PHENOTYPE; PATHOLOGY; RESPONSES;
D O I
10.1002/glia.23517
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) is a negative checkpoint regulator (NCR) involved in inhibition of T cell-mediated immunity. Expression changes of other NCRs (PD-1, PD-L1/L2, CTLA-4) during inflammation of the central nervous system (CNS) were previously demonstrated, but VISTA expression in the CNS has not yet been explored. Here, we report that in the human and mouse CNS, VISTA is most abundantly expressed by microglia, and to lower levels by endothelial cells. Upon TLR stimulation, VISTA expression was reduced in primary neonatal mouse and adult rhesus macaque microglia in vitro. In mice, microglial VISTA expression was reduced after lipopolysaccharide (LPS) injection, during experimental autoimmune encephalomyelitis (EAE), and in the accelerated aging Ercc1(Delta/-) mouse model. After LPS injection, decreased VISTA expression in mouse microglia was accompanied by decreased acetylation of lysine residue 27 in histone 3 in both its promoter and enhancer region. ATAC-sequencing indicated a potential regulation of VISTA expression by Pu.1 and Mafb, two transcription factors crucial for microglia function. Finally, our data suggested that VISTA expression was decreased in microglia in multiple sclerosis lesion tissue, whereas it was increased in Alzheimer's disease patients. This study is the first to demonstrate that in the CNS, VISTA is expressed by microglia, and that VISTA is differentially expressed in CNS pathologies.
引用
收藏
页码:2645 / 2658
页数:14
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