Deletion of inflammasome adaptor protein ASC enhances functional recovery after spinal cord injury in mice |
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| Authors: | Yasuyuki Shiraishi Atsushi Kimura Hiroaki Kimura Tsukasa Ohmori Masafumi Takahashi Katsushi Takeshita |
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| Institution: | 1. Department of Orthopaedics, Jichi Medical University School of Medicine, Tochigi, 329-0498, Japan;2. Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University School of Medicine, Tochigi, 329-0498, Japan;3. Department of Biochemistry, Jichi Medical University School of Medicine, Tochigi, 329-0498, Japan;1. Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan;2. Department of Musculoskeletal Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan;3. Department of Orthopaedic Surgery, Saitama Medical Center, Jichi Medical University, Japan;1. Faculty of Health Sciences, Hokkaido University, Hokkaido, Japan;2. Department of Rehabilitation, Sapporo Maruyama Orthopedic Hospital, Hokkaido, Japan;3. Department of Physical Therapy, Faculty of Health and Welfare, Prefectural University of Hiroshima, Hiroshima, Japan;4. Department of Orthopedic, Sapporo Maruyama Orthopedic Hospital, Hokkaido, Japan;1. Department of Orthopedic Surgery, Nihon University Hospital, Tokyo, Japan;2. Department of Rehabilitation Medicine, Yokohama City University Medical Center, Kanagawa, Japan;3. Department of Palliative and Supportive Medicine, Graduate School of Medicine, Aichi Medical University, Aichi, Japan;4. Department of Rehabilitation Medicine, Teikyo University School of Medicine University Hospital, Mizonokuchi, Japan;5. Department of Clinical Nutrition and Food Service, Yasuoka Hospital, Yamaguchi, Japan;6. Department of Physical Therapy, Kyorin University Hospital, Tokyo, Japan |
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| Abstract: | BackgroundResearch has revealed the crucial roles of inflammasomes in various central nervous system disorders. However, the role of inflammasomes in secondary damage following spinal cord injury (SCI) remains incompletely understood.MethodsHere, we investigated the role of apoptosis-associated speck-like protein (ASC), an adaptor protein for inflammasome formation, after contusion SCI in ASC homozygous knockout (ASC–/–) mice. Contusion SCI was induced using a force of 60 kdyn, and recovery of open-field locomotor performance was evaluated using the nine-point Basso Mouse Scale (BMS). Bone marrow transplantation (BMT) was performed to create mice chimeric for ASC expression in bone marrow cells.ResultsWestern blot analysis revealed that protein expression of NLRP3, ASC, Caspase-1, and IL-β were increased in injured spinal cords compared with sham-control spinal cords at 1 day post injury (dpi). Double immunostaining showed that ASC expression was co-localized to cellular constituents of the spinal cord, including NeuN+ neurons, CD11b+ microglia/macrophages, GFAP+ astrocytes, and MOG+ oligodendrocytes. ASC–/– mice had significantly better locomotor function assessed by BMS than wild-type (WT) mice. ASC–/– mice also had significantly reduced levels of Nlrp3, Casp1, IL1b, Il-6, Tnfa, Cxcl1, and Ly6g mRNA compared with WT mice. BMT (WT→ASC–/–) mice had significantly better BMS scores than BMT (WT→WT) mice. BMT (ASC–/–→WT) mice also had significantly better BMS scores than BMT (WT→WT) mice. However, the statistical significance was limited to time points between 7 and 21 dpi.ConclusionsThese results suggest that ASC-dependent inflammasome formation, especially in resident cells of the spinal cord, plays a pivotal role in the progression of secondary damage following SCI. |
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