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.
Highlights
In the injured adult mammalian CNS, the regenerative capacity of severed axons is very limited
Flow cytometry was used to assess the composition of injury-mobilized immune cell profiles in the nerve and dorsal root ganglia (DRG)
The distal nerve stump was identified by anti-GFAP staining, a protein upregulated in repair Schwann cells (Figure 1—figure supplement 2L)
Summary
In the injured adult mammalian CNS, the regenerative capacity of severed axons is very limited. Sciatic nerve injury leads to a remote and strong cell body response in axotomized DRG neurons (Chandran et al, 2016) This includes induction of neuron-intrinsic growth programs, neuronal release of cytokines and chemokines, activation of intra-ganglionic tissue resident macrophages, immune-like glia, and entry of hematogenous leukocytes (Cafferty et al, 2004; McLachlan and Hu, 2014; Richardson and Lu, 1994; Richardson et al, 2009; Wang et al, 2018; Zigmond and Echevarria, 2019). Our work provides novel insights into a rich and dynamic landscape of injury-associated cell states, and underscores the importance of properly orchestrated inflammation resolution in the nerve for neural repair
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