Dermal macrophages set pain sensitivity by modulating tissue NGF levels through SNX25–Nrf2 signaling
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- Tatsuhide Tanaka
- Nara Medical University
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- Hiroaki Okuda
- Kanazawa University
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- Yuki Terada
- Nara Medical University
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- Ayami Isonishi
- Nara Medical University
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- Masahiro Kitabatake
- Nara Medical University
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- Takeaki Shinjo
- Nara Medical University
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- Kazuya Nishimura
- Nara Medical University
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- Shoko Takemura
- Nara Medical University
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- Hidemasa Furue
- Hyogo College of Medicine
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- Kouko Tatsumi
- Nara Medical University
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- Akio Wanaka
- Nara Medical University
説明
<jats:title>Abstract</jats:title> <jats:p>Crosstalk between peripheral neurons and immune cells plays important roles in pain sensation. We identified sorting nexin 25 (Snx25) as a pain-modulating gene in a transgenic mouse line with reduced pain behavior. Snx25 conditional-KO (cKO) in monocyte/macrophage-lineage cells but not in the peripheral sensory neurons reduced pain responses in both normal and neuropathic conditions. Cross transplantation experiments of bone marrows between cKO and wild type (WT) mice revealed that cKO macrophages caused dull phenotype in WT mice and WT macrophages in turn increased pain behavior in cKO mice. SNX25 in dermal macrophages enhances NGF (one of the key factors in pain sensation) production by inhibiting ubiquitin-mediated degradation of Nrf2, a transcription factor that activates Ngf mRNA synthesis. We conclude that dermal macrophages set pain sensitivity by producing and secreting NGF into the dermis in addition to their host defense functions.</jats:p>