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

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

doi:10.1038/s41418-018-0098-3

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.

Highlights

We found that TIR domain-containing adaptor inducing interferon-β (TRIF) deficiency, but not myeloid differentiation factor 88 (MyD88) deficiency, substantially shortened the survival time of SOD1G93A mice (SOD1G93A/TRIF−/−, 138.4 ± 8.6 days; SOD1G93A/TRIF+/−, 147.0 ± 12.4 days; SOD1G93A, 156.6 ± 13.8 d; Fig. 1a, b), (SOD1G93A/MyD88−/−, 160.2 ± 11.2 days; SOD1G93A/MyD88+/−, 161.1 ± 13.0 days; SOD1G93A, 161.6 ± 11.3 days; Fig. 1c, d)
We demonstrate that elimination of the TRIFdependent Toll-like receptor (TLR) pathway accelerates disease progression of SOD1-amyotrophic lateral sclerosis (ALS) mice
SOD1-ALS mice with TRIF deletion (SOD1G93A/TRIF−/− mice) exhibited greater number of aberrantly activated astrocytes and microglia in the spinal cord compared to SOD1G93A mice

Summary

Introduction

One of the common pathological findings in ALS and other neurodegenerative diseases is neuroinflammation involving activated glial cells, such as microglia and astrocytes, along with infiltrating T-lymphocytes. These non-neuronal elements affect the fate of motor neurons through a “non-cell autonomous” mechanism [5,6,7]. Our previous works and those of others demonstrated that selective reduction of mutant SOD1 expression in microglia [8,9,10], astrocytes [11, 12], or oligodendrocytes [13] significantly slows the disease progression of mutant SOD1ALS mice. While the contributions of acquired immunity, such as effects mediated by T-lymphocytes, have been extensively investigated in ALS mice [16, 17], the functions of innate immune signaling pathways in ALS are still largely unknown

Methods

Results

Conclusion