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

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

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 3

The effects of IFN-γ on inflammatory infiltration.

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The effects of IFN-γ on inflammatory infiltration. (A and C) CD3 immunos...
(A and C) CD3 immunostaining showed that CNS delivery of IFN-γ reduced T cell infiltration in the lumbar spinal cords of mice on a Perk+/+ background at PID17, but did not significantly affect T cell infiltration in mice on a Perk+/– background. (B and C) CD11b immunostaining revealed that CNS delivery of IFN-γ did not significantly change the numbers of CD11b-positive microglia/macrophages in the lumbar spinal cord of mice on a Perk+/+ or Perk+/– background at PID17 (n = 3). (D) Real-time PCR analysis of the relative mRNA levels of CD3 and CD11b in the spinal cord at PID17 (n = 3). (E, F, and I) CD3 immunostaining showed that CNS delivery of IFN-γ did not affect T cell infiltration in lumbar spinal cord at PID14. (G, H, and I) CD11b immunostaining showed that CNS delivery of IFN-γ did not significantly change the numbers of CD11b-positive microglia/macrophages in the lumbar spinal cord at PID14 (n = 3). (J) Real-time PCR analysis of the relative mRNA levels of CD3 and CD11b in the spinal cord at PID14 (n = 4). (K) Real-time PCR analysis for the expression pattern of cytokines in the spinal cord at PID14 (n = 4). Scale bars: 50 μm. Error bars represent SD. *P < 0.05 versus IFN-γCNS–;Perk+/+.