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

Elife. 2020 Dec 2:9: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.

Keywords: axon regeneration; conditioning lesion; dorsal root ganglia; efferocytosis; mouse; neuroscience; scRNA sequencing; sciatic nerve injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cells, Cultured
  • Cytokine Receptor Common beta Subunit / genetics
  • Cytokine Receptor Common beta Subunit / metabolism
  • Disease Models, Animal
  • Female
  • Ganglia, Spinal / immunology*
  • Ganglia, Spinal / metabolism
  • Ganglia, Spinal / pathology
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Inflammation Mediators / metabolism
  • Leukocytes / immunology*
  • Leukocytes / metabolism
  • Leukocytes / pathology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes / immunology
  • Monocytes / metabolism
  • Nerve Regeneration*
  • Neuronal Outgrowth
  • Peripheral Nerve Injuries / genetics
  • Peripheral Nerve Injuries / immunology*
  • Peripheral Nerve Injuries / metabolism
  • Peripheral Nerve Injuries / pathology
  • Phagocytosis*
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Sciatic Nerve / immunology*
  • Sciatic Nerve / injuries
  • Sciatic Nerve / metabolism
  • Sciatic Nerve / pathology
  • Signal Transduction

Substances

  • Csf2ra protein, mouse
  • Cytokine Receptor Common beta Subunit
  • Inflammation Mediators
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Csf2rb protein, mouse
  • Granulocyte-Macrophage Colony-Stimulating Factor

Associated data

  • GEO/GSE153762