Department of Clinical Biochemistry, Molecular Sleep Laboratory, Rigshospitalet, Glostrup, Nordre Ringvej 57, 2600, Glostrup, Denmark.
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.
Mol Brain. 2018 Jul 3;11(1):36. doi: 10.1186/s13041-018-0380-9.
Major Histocompability Complex I (MHC-I) molecules present cellularly derived peptides to the adaptive immune system. Generally MHC-I is not expressed on healthy post-mitotic neurons in the central nervous system, but it is known to increase upon immune activation such as viral infections and also during neurodegenerative processes. MHC-I expression is known to be regulated by the DNA methyltransferase DNMT1 in non-neuronal cells. Interestingly DNMT1 expression is high in neurons despite these being non-dividing. This suggests a role for DNMT1 in neurons beyond the classical re-methylation of DNA after cell division. We thus investigated whether DNMT1 regulates MHC-I in post-mitotic neurons. For this we used primary cultures of mouse cerebellar granule neurons (CGNs). Our results showed that knockdown of DNMT1 in CGNs caused upregulation of some, but not all subtypes of MHC-I genes. This effect was synergistically enhanced by subsequent IFNγ treatment. Overall MHC-I protein level was not affected by knockdown of DNMT1 in CGNs. Instead our results show that the relative MHC-I expression levels among the different MHC subtypes is regulated by DNMT1 activity. In conclusion, we show that while the mouse H2-D1/L alleles are suppressed in neurons by DNMT1 activity under normal circumstances, the H2-K1 allele is not. This finding is particularly important in two instances. One: in the context of CNS autoimmunity with epitope presentation by specific MHC-I subtypes where this allele specific regulation might become important; and two: in amyotropic lateral sclerosis (ALS) where H2-K but not H2-D protects motor neurons from ALS astrocyte-induced toxicity in a mouse model of ALS.
主要组织相容性复合体 I (MHC-I) 分子将细胞内衍生的肽呈递给适应性免疫系统。通常情况下，中枢神经系统中健康的有丝分裂后神经元不表达 MHC-I，但已知在免疫激活（如病毒感染）期间以及神经退行性过程中会增加。MHC-I 的表达已知受到非神经元细胞中 DNA 甲基转移酶 DNMT1 的调节。有趣的是，尽管神经元不分裂，但 DNMT1 在神经元中的表达很高。这表明 DNMT1 在神经元中的作用超出了细胞分裂后 DNA 的经典再甲基化。因此，我们研究了 DNMT1 是否调节有丝分裂后神经元中的 MHC-I。为此，我们使用了小鼠小脑颗粒神经元 (CGN) 的原代培养物。我们的结果表明，CGN 中 DNMT1 的敲低导致一些，但不是所有 MHC-I 基因亚型的上调。这种效应随后被 IFNγ 处理协同增强。总体而言，CGN 中 DNMT1 的敲低并未影响 MHC-I 蛋白水平。相反，我们的结果表明，不同 MHC 亚型之间 MHC-I 表达水平的相对比例受 DNMT1 活性调节。总之，我们表明，虽然在正常情况下，DNMT1 活性会抑制神经元中的小鼠 H2-D1/L 等位基因，但不会抑制 H2-K1 等位基因。这一发现尤其重要，有两个原因。一：在 CNS 自身免疫的情况下，特定 MHC-I 亚型的表位呈递，这种等位基因特异性调节可能变得重要；二：在肌萎缩性侧索硬化症 (ALS) 中，H2-K 而不是 H2-D 保护运动神经元免受 ALS 星形胶质细胞诱导的毒性，在 ALS 的小鼠模型中。
