Abstract
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.
Highlights
Involvement of the immune system is a common trait in several neurodegenerative diseases and autoimmune diseases which affect the central nervous system (CNS) [1, 2], and the etiology of these neurological disorders is often not determined
To validate whether a similar regulation of Major Histocompability Complex (MHC)-I genes existed in mouse cells, we evaluated the expression of H2 genes in mouse N2a neuroblastoma cell lines upon 72 h of treatment with the inhibitor of DNA methyltransferase 1 gene (DNMT1) and DNA methylation 5-aza-2-deoxycytidine (5-aza)
We evaluated the gene expression compared to untreated cerebellar granule neurons (CGNs) for each of the genes of interests β2M, H2-K1, H2-D1 and H2-D1/L, as well as of the targeted genes DNMT1, DNMT3a and DNMT3b, upon treatment for 72 h with either non-targeting siRNA, siRNA against DNMT1, siRNA against DNMT3a, or siRNA against DNMT3b (Fig. 2a-e, bars from left to right on X-axis)
Summary
Involvement of the immune system is a common trait in several neurodegenerative diseases and autoimmune diseases which affect the central nervous system (CNS) [1, 2], and the etiology of these neurological disorders is often not determined. MHC class I signaling has been suggested to play a role in neurodegenerative disorders such as Parkinson’s disease and Amyotrophic Lateral Sclerosis (ALS) [5, 6]. A range of autoimmune CNS diseases involving neuronal destruction is likely mediated by CD8+ T cells, as suggested by the presence of CD8+ T cells in affected brain areas in Rasmussen’s encephalitis [10], paraneoplastic neuronal degeneration [11], and Multiple Sclerosis [12] which is otherwise considered a CD4+ T cell driven disease.
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