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Cell. 2019 Feb 7;176(4):716-728.e18. doi: 10.1016/j.cell.2018.12.022. Epub 2019 Jan 31.

Natural Killer Cells Degenerate Intact Sensory Afferents following Nerve Injury.

Author information

1
Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul 03080, Republic of Korea; Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
2
Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea.
3
Departments of Anesthesia and Neurobiology, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
4
Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul 03080, Republic of Korea.
5
Departments of Physiology, Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Republic of Korea.
6
Department of Physiology, Seoul National University College of Medicine, Seoul 03087, Republic of Korea.
7
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
8
Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France.
9
Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul 03080, Republic of Korea; Departments of Physiology, Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Republic of Korea.
10
Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 700-412, Korea.
11
Neurosurgery Department, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
12
Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
13
Departments of Anesthesia and Neurobiology, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA. Electronic address: michael.costigan@childrens.harvard.edu.
14
Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul 03080, Republic of Korea; Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: odolbae@snu.ac.kr.

Abstract

Sensory axons degenerate following separation from their cell body, but partial injury to peripheral nerves may leave the integrity of damaged axons preserved. We show that an endogenous ligand for the natural killer (NK) cell receptor NKG2D, Retinoic Acid Early 1 (RAE1), is re-expressed in adult dorsal root ganglion neurons following peripheral nerve injury, triggering selective degeneration of injured axons. Infiltration of cytotoxic NK cells into the sciatic nerve by extravasation occurs within 3 days following crush injury. Using a combination of genetic cell ablation and cytokine-antibody complex stimulation, we show that NK cell function correlates with loss of sensation due to degeneration of injured afferents and reduced incidence of post-injury hypersensitivity. This neuro-immune mechanism of selective NK cell-mediated degeneration of damaged but intact sensory axons complements Wallerian degeneration and suggests the therapeutic potential of modulating NK cell function to resolve painful neuropathy through the clearance of partially damaged nerves.

KEYWORDS:

Wallerian degeneration; autoimmunity; dorsal root ganglia; innate immunity; natural cytotoxicity; neurodegeneration; neuroimmune; neuropathic pain; peripheral neuropathy; sciatic nerve crush

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