TY - JOUR
T1 - Deletion of CD38 suppresses glial activation and neuroinflammation in a mouse model of demyelination
AU - Roboon, Jureepon
AU - Hattori, Tsuyoshi
AU - Ishii, Hiroshi
AU - Takarada-Iemata, Mika
AU - Le, Thuong Manh
AU - Shiraishi, Yoshitake
AU - Ozaki, Noriyuki
AU - Yamamoto, Yasuhiko
AU - Sugawara, Akira
AU - Okamoto, Hiroshi
AU - Higashida, Haruhiro
AU - Kitao, Yasuko
AU - Hori, Osamu
N1 - Funding Information:
This work was supported by Grants-in Aid for Scientific Research (18K06501 to TH, 18K06500 to OH, 17K10821 to HI, and 18K06463 to MT-I) from the Ministry of Education, Science, Technology, Sports and Culture of Japan, and by Kanazawa University SAKIGAKE project 2018 and CHOZEN project.
Publisher Copyright:
© 2019 Roboon, Hattori, Ishii, Takarada-Iemata, Le, Shiraishi, Ozaki, Yamamoto, Sugawara, Okamoto, Higashida, Kitao and Hori.
PY - 2019/5/14
Y1 - 2019/5/14
N2 - CD38 is an enzyme that catalyzes the synthesis of cyclic adenosine diphosphate-ribose from nicotinamide adenine dinucleotide (NAD+). We recently reported that this molecule regulates the maturation and differentiation of glial cells such as astrocytes and oligodendrocytes (OLs) in the developing brain. To analyze its role in the demyelinating situation, we employed cuprizone (CPZ)-induced demyelination model in mice, which is characterized by oligodendrocyte-specific apoptosis, followed by the strong glial activation, demyelination, and repopulation of OLs. By using this model, we found that CD38 was upregulated in both astrocytes and microglia after CPZ administration. Experiments using wild-type and CD38 knockout (KO) mice, together with those using cultured glial cells, revealed that CD38 deficiency did not affect the initial decrease of the number of OLs, while it attenuated CPZ-induced demyelination, and neurodegeneration. Importantly, the clearance of the degraded myelin and oligodendrocyte repopulation were also reduced in CD38 KO mice. Further experiments revealed that these observations were associated with reduced levels of glial activation and inflammatory responses including phagocytosis, most likely through the enhanced level of NAD+ in CD38-deleted condition. Our results suggest that CD38 and NAD+ in the glial cells play a critical role in the demyelination and subsequent oligodendrocyte remodeling through the modulation of glial activity and neuroinflammation.
AB - CD38 is an enzyme that catalyzes the synthesis of cyclic adenosine diphosphate-ribose from nicotinamide adenine dinucleotide (NAD+). We recently reported that this molecule regulates the maturation and differentiation of glial cells such as astrocytes and oligodendrocytes (OLs) in the developing brain. To analyze its role in the demyelinating situation, we employed cuprizone (CPZ)-induced demyelination model in mice, which is characterized by oligodendrocyte-specific apoptosis, followed by the strong glial activation, demyelination, and repopulation of OLs. By using this model, we found that CD38 was upregulated in both astrocytes and microglia after CPZ administration. Experiments using wild-type and CD38 knockout (KO) mice, together with those using cultured glial cells, revealed that CD38 deficiency did not affect the initial decrease of the number of OLs, while it attenuated CPZ-induced demyelination, and neurodegeneration. Importantly, the clearance of the degraded myelin and oligodendrocyte repopulation were also reduced in CD38 KO mice. Further experiments revealed that these observations were associated with reduced levels of glial activation and inflammatory responses including phagocytosis, most likely through the enhanced level of NAD+ in CD38-deleted condition. Our results suggest that CD38 and NAD+ in the glial cells play a critical role in the demyelination and subsequent oligodendrocyte remodeling through the modulation of glial activity and neuroinflammation.
KW - Cuprizone
KW - Demyelination
KW - Gliosis
KW - NAD
KW - Neuroinflammation
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U2 - 10.3389/fncel.2019.00258
DO - 10.3389/fncel.2019.00258
M3 - Article
AN - SCOPUS:85068560945
VL - 13
JO - Frontiers in Cellular Neuroscience
JF - Frontiers in Cellular Neuroscience
SN - 1662-5102
M1 - 258
ER -