Analysis of the immune response to sciatic nerve injury identifies efferocytosis as a key mechanism of nerve debridement
- University of Michigan Medical School, United States
- University of California, Los Angeles, United States
- Burke Neurological Institute, United States
- The Ohio State University Wexner Medical Center, United States
- University of Michigan School of Medicine, United States
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.
Data availability
The bulk RNA-seq and scRNA-seq data is available online in the Gene Expression Omnibus (GEO) database (GSE153762).
Article and author information
Author details
Edmund R Hollis II
Daniel H Geschwind
Funding
New York State Department of Health (C33267GG)
- Edmund R Hollis II
- Roman Giger
National Eye Institute (R01EY029159)
- Benjamin M Segal
- Roman Giger
National Eye Institute (R01EY028350)
- Benjamin M Segal
- Roman 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 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
- Brandon K Harvey, NIDA/NIH, United States
Publication history
- Received: June 19, 2020
- Accepted: December 1, 2020
- Accepted Manuscript published: December 2, 2020 (version 1)
- Accepted Manuscript updated: December 7, 2020 (version 2)
- 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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Analysis of the immune response to sciatic nerve injury identifies efferocytosis as a key mechanism of nerve debridement
eLife 9:e60223.
https://doi.org/10.7554/eLife.60223
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