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The integrated stress response prevents demyelination by protecting oligodendrocytes against immune-mediated damage
Wensheng Lin, … , Stephen D. Miller, Brian Popko
Wensheng Lin, … , Stephen D. Miller, Brian Popko
Published February 1, 2007
Citation Information: J Clin Invest. 2007;117(2):448-456. https://doi.org/10.1172/JCI29571.
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Research Article Article has an altmetric score of 10

The integrated stress response prevents demyelination by protecting oligodendrocytes against immune-mediated damage

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Abstract

In response to ER stress, the pancreatic endoplasmic reticulum kinase (PERK) coordinates an adaptive program known as the integrated stress response (ISR) by phosphorylating the α subunit of eukaryotic translation initiation factor 2 (eIF2α). IFN-γ, which activates the ER stress response in oligodendrocytes, is believed to play a critical role in the immune-mediated CNS disorder multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). Here we report that CNS delivery of IFN-γ before EAE onset ameliorated the disease course and prevented demyelination, axonal damage, and oligodendrocyte loss. The beneficial effects of IFN-γ were accompanied by PERK activation in oligodendrocytes and were abrogated in PERK-deficient animals. Our results indicate that IFN-γ activation of PERK in mature oligodendrocytes attenuates EAE severity and suggest that therapeutic approaches to activate the ISR could prove beneficial in MS.

Authors

Wensheng Lin, Samantha L. Bailey, Hanson Ho, Heather P. Harding, David Ron, Stephen D. Miller, Brian Popko

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Figure 2

CNS delivery of IFN-γ before EAE onset protects against EAE-induced demyelination dependent on the PERK pathway.

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CNS delivery of IFN-γ before EAE onset protects against EAE-induced demy...
(A) MBP immunostaining showed that the CNS delivery of IFN-γ protected against EAE-induced demyelination in the lumbar spinal cords of mice on a Perk+/+ background at PID17. In contrast, there was more severe demyelination in the lumbar spinal cord of IFN-γCNS+;Perk+/– mice at PID17 compared with control mice. Scale bar: 50 μm. (B and C) Toluidine blue staining revealed that the myelin and axons in the spinal cords of IFN-γCNS+;Perk+/+ mice remained almost intact at PID17. In contrast, CNS delivery of IFN-γ did not prevent demyelination and axon damage in the lumbar spinal cord of mice on a Perk+/–background at PID17. Scale bar: 10 μm. (D and E) CC1 immunostaining showed that oligodendrocytes in the lumbar spinal cords of IFN-γCNS+;Perk+/+ mice remained almost intact at PID17. In contrast, similar to control mice, IFN-γCNS+;Perk+/– mice lost the majority of oligodendrocytes in the demyelinated lesions of their lumbar spinal cords at PID17. Scale bar: 25 μm. (F) Real-time PCR analysis of the mRNA level of MBP in the indicated spinal cords at PID17 relative to that in the spinal cords of age-matched naive mice. Error bars represent SD. n = 3. *P < 0.05 versus IFN-γCNS–;PERK+/+ (C) or naive mice (E and F).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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