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Analysis of the Immune Response to Sciatic Nerve Injury Identifies Efferocytosis as a Key Mechanism of Nerve Debridement

View ORCID ProfileAshley L. Kalinski, Choya Yoon, Lucas D. Huffman, View ORCID ProfilePatrick C. Duncker, View ORCID ProfileRafi Kohen, Ryan Passino, Hannah Hafner, Craig Johnson, View ORCID ProfileRiki Kawaguchi, Kevin S. Carbajal, Juan Sebastián Jara, View ORCID ProfileEdmund Hollis, Daniel H. Geschwind, View ORCID ProfileBenjamin M. Segal, View ORCID ProfileRoman J. Giger
doi: https://doi.org/10.1101/2020.10.23.352872
Ashley L. Kalinski
1Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109-2200
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  • ORCID record for Ashley L. Kalinski
Choya Yoon
1Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109-2200
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Lucas D. Huffman
1Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109-2200
3Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109-2200
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Patrick C. Duncker
2Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109-2200
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Rafi Kohen
1Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109-2200
3Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109-2200
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Ryan Passino
1Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109-2200
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Hannah Hafner
1Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109-2200
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Craig Johnson
1Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109-2200
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Riki Kawaguchi
4Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
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Kevin S. Carbajal
2Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109-2200
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Juan Sebastián Jara
5Burke Neurological Institute, White Plains, NY 10605
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Edmund Hollis
5Burke Neurological Institute, White Plains, NY 10605
6The Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065
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Daniel H. Geschwind
4Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
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Benjamin M. Segal
7Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH 43210
8The Neurological Institute, The Ohio State University
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Roman J. Giger
1Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109-2200
2Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109-2200
3Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109-2200
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  • ORCID record for Roman J. Giger
  • For correspondence: rgiger@umich.edu
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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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • This version of the manuscript has been revised to update the co-author list.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 24, 2020.
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Analysis of the Immune Response to Sciatic Nerve Injury Identifies Efferocytosis as a Key Mechanism of Nerve Debridement
Ashley L. Kalinski, Choya Yoon, Lucas D. Huffman, Patrick C. Duncker, Rafi Kohen, Ryan Passino, Hannah Hafner, Craig Johnson, Riki Kawaguchi, Kevin S. Carbajal, Juan Sebastián Jara, Edmund Hollis, Daniel H. Geschwind, Benjamin M. Segal, Roman J. Giger
bioRxiv 2020.10.23.352872; doi: https://doi.org/10.1101/2020.10.23.352872
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Analysis of the Immune Response to Sciatic Nerve Injury Identifies Efferocytosis as a Key Mechanism of Nerve Debridement
Ashley L. Kalinski, Choya Yoon, Lucas D. Huffman, Patrick C. Duncker, Rafi Kohen, Ryan Passino, Hannah Hafner, Craig Johnson, Riki Kawaguchi, Kevin S. Carbajal, Juan Sebastián Jara, Edmund Hollis, Daniel H. Geschwind, Benjamin M. Segal, Roman J. Giger
bioRxiv 2020.10.23.352872; doi: https://doi.org/10.1101/2020.10.23.352872

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