1. Neuroscience
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Analysis of the immune response to sciatic nerve injury identifies efferocytosis as a key mechanism of nerve debridement

  1. Ashley L Kalinski
  2. Choya Yoon
  3. Lucas D Huffman
  4. Patrick C Duncker
  5. Rafi Kohen
  6. Ryan Passino
  7. Hannah Hafner
  8. Craig Johnson
  9. Riki Kawaguchi
  10. Kevin S Carbajal
  11. Juan Sebastian Jara
  12. Edmund R Hollis II
  13. Daniel H Geschwind
  14. Benjamin M Segal
  15. Roman J Giger  Is a corresponding author
  1. University of Michigan Medical School, United States
  2. University of California, Los Angeles, United States
  3. Burke Neurological Institute, United States
  4. The Ohio State University Wexner Medical Center, United States
  5. University of Michigan School of Medicine, United States
Research Article
  • Cited 1
  • Views 1,310
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Cite this article as: eLife 2020;9:e60223 doi: 10.7554/eLife.60223

Abstract

Sciatic nerve crush injury triggers sterile inflammation within the distal nerve and axotomized dorsal root ganglia (DRGs). Granulocytes and pro-inflammatory Ly6Chigh monocytes infiltrate the nerve first, and rapidly give way to Ly6Cnegative inflammation-resolving macrophages. In axotomized DRGs, few hematogenous leukocytes are detected and resident macrophages acquire a ramified morphology. Single-cell RNA-sequencing of injured sciatic nerve identifies five macrophage subpopulations, repair Schwann cells, and mesenchymal precursor cells. Macrophages at the nerve crush site are molecularly distinct from macrophages associated with Wallerian degeneration. In the injured nerve, macrophages 'eat' apoptotic leukocytes, a process called efferocytosis, and thereby promote an anti-inflammatory milieu. Myeloid cells in the injured nerve, but not axotomized DRGs, strongly express receptors for the cytokine GM-CSF. In GM-CSF deficient (Csf2-/-) mice, inflammation resolution is delayed and conditioning-lesion induced regeneration of DRG neuron central axons is abolished. Thus, carefully orchestrated inflammation resolution in the nerve is required for conditioning-lesion induced neurorepair.

Article and author information

Author details

  1. Ashley L Kalinski

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7611-0810

  2. Choya Yoon

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Lucas D Huffman

    Department of Cell and Developmental Biology; Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Patrick C Duncker

    Department of Neurology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Rafi Kohen

    Department of Cell and Developmental Biology; Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Ryan Passino

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Hannah Hafner

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Craig Johnson

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Riki Kawaguchi

    Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Kevin S Carbajal

    Department of Neurology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Juan Sebastian Jara

    Research, Burke Neurological Institute, White Plains, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. Edmund R Hollis II

    Research, Burke Neurological Institute, White Plains, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4535-4668

  13. Daniel H Geschwind

    Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2896-3450

  14. Benjamin M Segal

    Department of Neurology; The Neurological Institute, The Ohio State University Wexner Medical Center, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.

  15. Roman J Giger

    Cellular & Developmental Biology, University of Michigan School of Medicine, Ann Arbor, United States
    For correspondence
    rgiger@med.umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2926-3336

Funding

New York State Department of Health (C33267GG)

  • Edmund R Hollis II
  • Roman J Giger

National Eye Institute (R01EY029159)

  • Benjamin M Segal
  • Roman J Giger

National Eye Institute (R01EY028350)

  • Benjamin M Segal
  • Roman J Giger

National Institute of Neurological Disorders and Stroke (T32 NS07222)

  • Ashley L Kalinski

National Institute of General Medical Sciences (T32-GM113900)

  • Lucas D Huffman

Wings for Life (fellowship)

  • Choya Yoon

Dr Miriam and Sheldon G. Adelson Medical Research Foundation (Program)

  • Riki Kawaguchi
  • Daniel H Geschwind
  • Roman J Giger

Stanley D. and Joan H. Ross Chair in Neuromodulation fund

  • Benjamin M Segal

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal research was approved by the University of Michigan School of Medicine and conducted under the IACUC approved protocol PRO00007948

Reviewing Editor

  1. Brandon K Harvey, NIDA/NIH, United States

Publication history

  1. Received: June 19, 2020
  2. Accepted: December 1, 2020
  3. Accepted Manuscript published: December 2, 2020 (version 1)
  4. Accepted Manuscript updated: December 7, 2020 (version 2)
  5. Version of Record published: December 14, 2020 (version 3)

Copyright

© 2020, Kalinski et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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