Rissiek Björn, Stabernack Joschi, Cordes Maike, Duan Yinghui, Behr Sarah, Menzel Stephan, Magnus Tim, Koch-Nolte Friedrich
Department of Neurology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Institute of Immunology at University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Front Mol Neurosci. 2020 Jan 14;12:330. doi: 10.3389/fnmol.2019.00330. eCollection 2019.
ADP-ribosylation of the P2X7k splice variant on mouse T cells by Ecto-ADP-ribosyltransferase ARTC2.2 in response to its substrate extracellular nicotinamide adenine dinucleotide (NAD) triggers cell death. Since NAD is released as a danger signal during tissue damage, this NAD-induced cell death (NICD) may impact the survival of other cell populations co-expressing P2X7 and of one of the ARTC2 isoforms (ARTC2.1, ARTC2.2). NICD of brain-resident, non-T cell populations has only been rudimentarily investigated. In this study, we evaluated the susceptibility of two glia cell populations, astrocytes and microglia, towards NICD. We found that astrocytes and microglia strongly upregulate cell surface levels of ARTC2.1 and ADP-ribosylation of cell surface proteins in response to treatment with lipopolysaccharide (LPS) and the mitogen-activated protein kinase kinase (MEK) 1 and 2 inhibitor U0126, but do not respond to extracellular NAD with P2X7 activation and induction of cell death. Furthermore, we found that astrocytes and microglia preferentially express the ADP-ribosylation-insensitive P2X7a splice variant, likely accounting for the resistance of these cells to NICD.
胞外ADP-核糖基转移酶ARTC2.2对小鼠T细胞上P2X7k剪接变体进行ADP-核糖基化，以响应其底物细胞外烟酰胺腺嘌呤二核苷酸（NAD），从而触发细胞死亡。由于NAD在组织损伤期间作为危险信号释放，这种NAD诱导的细胞死亡（NICD）可能会影响共表达P2X7和ARTC2同工型之一（ARTC2.1、ARTC2.2）的其他细胞群体的存活。脑内非T细胞群体的NICD仅得到初步研究。在本研究中，我们评估了两种神经胶质细胞群体，即星形胶质细胞和小胶质细胞对NICD的易感性。我们发现，星形胶质细胞和小胶质细胞在受到脂多糖（LPS）和丝裂原活化蛋白激酶激酶（MEK）1和2抑制剂U0126处理后，会强烈上调ARTC2.1的细胞表面水平和细胞表面蛋白的ADP-核糖基化，但对细胞外NAD不会通过P2X7激活和诱导细胞死亡做出反应。此外，我们发现星形胶质细胞和小胶质细胞优先表达对ADP-核糖基化不敏感的P2X7a剪接变体，这可能是这些细胞对NICD具有抗性的原因。
