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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 26070-26084 |
| Number of pages | 15 |
| Journal | Journal of Biological Chemistry |
| Volume | 284 |
| Issue number | 38 |
| DOIs | |
| State | Published - Sep 18 2009 |
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ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
- Medicine(all)
Cite this
PARP-1 deficiency increases the severity of disease in a mouse model of multiple sclerosis. / Selvaraj, Vimal; Soundapandian, Mangala M.; Chechneva, Olga; Williams, Ambrose J.; Sidorov, Maxim K.; Soulika, Athena; Pleasure, David E; Deng, Wenbin.
In: Journal of Biological Chemistry, Vol. 284, No. 38, 18.09.2009, p. 26070-26084.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - PARP-1 deficiency increases the severity of disease in a mouse model of multiple sclerosis
AU - Selvaraj, Vimal
AU - Soundapandian, Mangala M.
AU - Chechneva, Olga
AU - Williams, Ambrose J.
AU - Sidorov, Maxim K.
AU - Soulika, Athena
AU - Pleasure, David E
AU - Deng, Wenbin
PY - 2009/9/18
Y1 - 2009/9/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=70350005154&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70350005154&partnerID=8YFLogxK
U2 - 10.1074/jbc.M109.013474
DO - 10.1074/jbc.M109.013474
M3 - Article
C2 - 19628872
AN - SCOPUS:70350005154
VL - 284
SP - 26070
EP - 26084
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 38
ER -