Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes

Okiru Komine, Hirofumi Yamashita, Noriko Fujimori-Tonou, Masato Koike, Shijie Jin, Yasuhiro Moriwaki, Fumito Endo, Seiji Watanabe, Satoshi Uematsu, Shizuo Akira, Yasuo Uchiyama, Ryosuke Takahashi, Hidemi Misawa, Koji Yamanaka

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

There is compelling evidence that glial-immune interactions contribute to the progression of neurodegenerative diseases. The adaptive immune response has been implicated in disease processes of amyotrophic lateral sclerosis (ALS), but it remains unknown if innate immune signaling also contributes to ALS progression. Here we report that deficiency of the innate immune adaptor TIR domain-containing adaptor inducing interferon-β (TRIF), which is essential for certain Toll-like receptor (TLR) signaling cascades, significantly shortens survival time and accelerates disease progression of ALS mice. While myeloid differentiation factor 88 (MyD88) is also a crucial adaptor for most TLR signaling pathways, MyD88 deficiency had only a marginal impact on disease course. Moreover, TRIF deficiency reduced the number of natural killer (NK), NK-T-lymphocytes, and CD8-T cells infiltrating into the spinal cord of ALS mice, but experimental modulation of these populations did not substantially influence survival time. Instead, we found that aberrantly activated astrocytes expressing Mac2, p62, and apoptotic markers were accumulated in the lesions of TRIF-deficient ALS mice, and that the number of aberrantly activated astrocytes was negatively correlated with survival time. These findings suggest that TRIF pathway plays an important role in protecting a microenvironment surrounding motor neurons by eliminating aberrantly activated astrocytes.

Original languageEnglish
Pages (from-to)1-17
Number of pages17
JournalCell Death and Differentiation
DOIs
Publication statusAccepted/In press - 2018 Mar 22

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Deficiency Diseases
Amyotrophic Lateral Sclerosis
Astrocytes
Disease Progression
Myeloid Differentiation Factor 88
Toll-Like Receptors
T-Lymphocytes
Motor Neurons
Adaptive Immunity
Neuroglia
Neurodegenerative Diseases
Interferons
Spinal Cord
Population

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes. / Komine, Okiru; Yamashita, Hirofumi; Fujimori-Tonou, Noriko; Koike, Masato; Jin, Shijie; Moriwaki, Yasuhiro; Endo, Fumito; Watanabe, Seiji; Uematsu, Satoshi; Akira, Shizuo; Uchiyama, Yasuo; Takahashi, Ryosuke; Misawa, Hidemi; Yamanaka, Koji.

In: Cell Death and Differentiation, 22.03.2018, p. 1-17.

Research output: Contribution to journalArticle

Komine, O, Yamashita, H, Fujimori-Tonou, N, Koike, M, Jin, S, Moriwaki, Y, Endo, F, Watanabe, S, Uematsu, S, Akira, S, Uchiyama, Y, Takahashi, R, Misawa, H & Yamanaka, K 2018, 'Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes', Cell Death and Differentiation, pp. 1-17. https://doi.org/10.1038/s41418-018-0098-3
Komine, Okiru ; Yamashita, Hirofumi ; Fujimori-Tonou, Noriko ; Koike, Masato ; Jin, Shijie ; Moriwaki, Yasuhiro ; Endo, Fumito ; Watanabe, Seiji ; Uematsu, Satoshi ; Akira, Shizuo ; Uchiyama, Yasuo ; Takahashi, Ryosuke ; Misawa, Hidemi ; Yamanaka, Koji. / Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes. In: Cell Death and Differentiation. 2018 ; pp. 1-17.
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