PARP-1 Deficiency Increases the Severity of Disease in a Mouse Model of Multiple Sclerosis

Vimal Selvaraj,Mangala M Soundarapandian,Olga Chechneva,Ambrose J Williams,Maxim K Sidorov,Athena M Soulika,David E Pleasure,Wenbin Deng

doi:10.1074/jbc.m109.013474

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) has been implicated in the pathogenesis of several central nervous system (CNS) disorders. However, the role of PARP-1 in autoimmune CNS injury remains poorly understood. Therefore, we studied experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis in mice with a targeted deletion of PARP-1. We identified inherent physiological abnormalities in the circulating and splenic immune composition between PARP-1(-/-) and wild type (WT) mice. Upon EAE induction, PARP-1(-/-) mice had an earlier onset and developed a more severe EAE compared with WT cohorts. Splenic response was significantly higher in PARP-1(-/-) mice largely because of B cell expansion. Although formation of Th1 and Th17 effector T lymphocytes was unaffected, PARP-1(-/-) mice had significantly earlier CD4+ T lymphocyte and macrophage infiltration into the CNS during EAE. However, we did not detect significant differences in cytokine profiles between PARP-1(-/-) and WT spinal cords at the peak of EAE. Expression analysis of different PARP isozymes in EAE spinal cords showed that PARP-1 was down-regulated in WT mice and that PARP-3 but not PARP-2 was dramatically up-regulated in both PARP-1(-/-) and WT mice, suggesting that these PARP isozymes could have distinct roles in different CNS pathologies. Together, our results indicate that PARP-1 plays an important role in regulating the physiological immune composition and in immune modulation during EAE; our finding identifies a new aspect of immune regulation by PARPs in autoimmune CNS pathology.

Highlights

Mice lacking Poly(ADP-ribose) polymerase-1 (PARP-1) (PARP-1Ϫ/Ϫ) have shown significant protection against various forms of central nervous system (CNS) injury [26]
Clinical reactions for TNF␣, IFN␥, IL-1␤, IL-2, IL-4, IL-5, IL-10, iNOS, signs of EAE were evident by Day 11 in PARP-1Ϫ/Ϫ compared and TGF␤ were performed in triplicate on a Roche Lightcycler with Day 13 in wild type (WT) mice
Several studies have suggested that PARP-1 is a potential therapeutic target for the treatment of autoimmune diseases including multiple sclerosis [37, 38], the specific role of PARP-1 in disease development and progression has not been studied

Summary

Introduction

Mice lacking PARP-1 (PARP-1Ϫ/Ϫ) have shown significant protection against various forms of CNS injury [26]. Subsets of spleen and lymph node CD4ϩ T lymphocytes that polarize to IL-17-producing T helper type 17 (Th17) cells were not significantly different between PARP-1Ϫ/Ϫ and WT mice at both Day 7 (Fig. 3A) and Day 10 (Fig. 3B) of EAE.

Results

Conclusion