PARP-1 deregulation in multiple sclerosis

Abstract

Background: Poly (ADP-ribose) polymerase 1 (PARP-1) plays pivotal roles in immune and inflammatory responses. Accumulating evidence suggests PARP-1 as a promising target for immunomodulation in multiple sclerosis and natalizumab-associated progressive multifocal leukoencephalopathy.

Objective: This study explores expression of PARP-1 and downstream effectors in multiple sclerosis and during natalizumab treatment.

Methods: Transcriptional expressions were studied by real-time reverse transcriptase polymerase chain reaction on CD4⁺T/CD8⁺T/CD14⁺/B cells and peripheral blood mononuclear cells from healthy volunteers, untreated and natalizumab-treated non-progressive multifocal leukoencephalopathy and progressive multifocal leukoencephalopathy multiple sclerosis patients.

Results: PARP-1 expression was higher in CD4⁺T, CD8⁺T and B cells from untreated patients compared to healthy volunteers. Natalizumab treatment restored deregulated PARP-1 expression in T cells but not in B cells. Sustained upregulation of PARP-1 was associated with decreased expression of downstream PARP-1 factors such as TGFBR1/TGFBR2/BCL6 in B cells. Notably, a higher expression of PARP-1 was detected in progressive multifocal leukoencephalopathy patients.

Conclusions: Given the importance of PARP-1 in inflammatory processes, its upregulation in multiple sclerosis lymphocyte populations suggests a potential role in the immune pathogenesis of multiple sclerosis. Strikingly higher PARP-1 expression in progressive multifocal leukoencephalopathy cases suggests its involvement in progressive multifocal leukoencephalopathy disease pathomechanisms. These results further support the value of PARP-1 inhibitors as a potential novel therapeutic strategy for multiple sclerosis and natalizumab-associated progressive multifocal leukoencephalopathy.

Keywords: JCV; PARP-1; multiple sclerosis; natalizumab; progressive multifocal leukoencephalopathy (PML).

Figure 1.

Expression of poly (ADP-ribose) polymerase 1 (PARP-1) mRNA in CD4⁺T, CD8⁺T, B cells and monocytes. Transcriptional expression of PARP-1 was analysed with real-time reverse transcriptase polymerase chain reaction in CD4⁺T (a), CD8⁺T cells (b), B cells (c) and monocytes (d) from healthy volunteer, untreated patients and natalizumab-treated patients (3–24 months or >24 months). Relative expression levels (median with interquartile range) are depicted. ****P < 0.0001; ***P < 0.001; **P < 0.01; *P < 0.05.

Figure 2.

Expression of TGFBR1 and TGFBR2 mRNA in CD4⁺T and B cells. Transcriptional expressions of TGFBR1 (left panels) and TGFBR2 (right panels) were analysed with real-time reverse transcriptase polymerase chain reaction in CD4⁺T (a) and B cells (b) from healthy volunteers, untreated and natalizumab-treated patients (3–24 months; >24 months). Relative expression levels (median with interquartile range) are depicted. ***P < 0.001; **P < 0.01, *P < 0.05; ns: not significant.

Figure 3.

Expression of BCL6 mRNA in B cells and CD8⁺T cells. Transcriptional expression of BCL6 was analysed with real-time reverse transcriptase polymerase chain reaction in B cells (a) and CD8⁺T cells (b) from healthy volunteers, untreated and natalizumab-treated patients (3–24 months; >24 months). Relative expression levels (median with interquartile range) are depicted. ***P < 0.001; **P < 0.01; *P < 0.05; ns: not significant.

Figure 4.

Expression of poly (ADP-ribose) polymerase 1 (PARP-1), TGFBR1 and TGFBR2 mRNA in peripheral blood mononuclear cells (PBMCs). Transcriptional expression of PARP-1 (a), TGFBR1 ((b), left panel) and TGFBR2 ((b), right panel) were analysed with real-time reverse transcriptase polymerase chain reaction in PBMCs from healthy volunteers, untreated, natalizumab-treated patients (3–24 months; >24 months) and natalizumab-associated progressive multifocal leukoencephalopathy (PML) patients. Relative expression levels (median with interquartile range) are depicted. ****P < 0.0001; ***P < 0.001; **P < 0.01; *P < 0.05; ns: not significant.