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Dermal macrophages set pain sensitivity by modulating the amount of tissue NGF through an SNX25-Nrf2 pathway

Tatsuhide Tanaka1, Hiroaki Okuda2, Ayami Isonishi3

  • 1Department of Anatomy and Neuroscience, Faculty of Medicine, Nara Medical University, Kashihara, Japan. ttanaka@naramed-u.ac.jp.

Nature Immunology
|January 26, 2023
PubMed

Insights

Sorting nexin 25 (SNX25) in macrophages regulates pain sensitivity. Deleting SNX25 in these immune cells reduces pain by controlling nerve growth factor (NGF) levels.

Area of Science:

  • Neuroscience
  • Immunology
  • Molecular Biology

Background:

  • Peripheral neuron-immune cell interactions are crucial for pain sensation.
  • Identifying genes that modulate pain sensitivity is essential for understanding pain mechanisms.

Purpose of the Study:

  • To investigate the role of sorting nexin 25 (SNX25) in pain modulation.
  • To determine whether SNX25 in immune cells influences pain sensitivity.

Main Methods:

  • Generated conditional knockout mice (Snx25cKO) with SNX25 deleted in monocytes and macrophages.
  • Utilized bone marrow transplantation experiments to assess macrophage contribution to pain sensitivity.
  • Analyzed the molecular mechanisms involving SNX25, Nrf2, and nerve growth factor (NGF) in dermal macrophages.

Main Results:

  • Conditional deletion of SNX25 in macrophages reduced pain responses in both normal and neuropathic states.
  • Bone marrow transplantation confirmed that macrophages modulate pain sensitivity.
  • SNX25 in dermal macrophages promotes NGF expression by inhibiting Nrf2 degradation, thereby influencing pain thresholds.

Conclusions:

  • Dermal macrophages regulate pain sensitivity through NGF production, modulated by SNX25.
  • SNX25 is a key molecular player in the immune system's control of pain perception.

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