Neutrophils Are Critical for Myelin Removal in a Peripheral Nerve Injury Model of Wallerian Degeneration

Abstract

Wallerian degeneration (WD) is considered an essential preparatory stage to the process of axonal regeneration. In the peripheral nervous system, infiltrating monocyte-derived macrophages, which use the chemokine receptor CCR2 to gain entry to injured tissues from the bloodstream, are purportedly necessary for efficient WD. However, our laboratory has previously reported that myelin clearance in the injured sciatic nerve proceeds unhindered in the Ccr2Ϫ / Ϫ mouse model. Here, we extensively characterize WD in male Ccr2Ϫ / Ϫ mice and identify a compensatory mechanism of WD that is facilitated primarily by neutrophils. In response to the loss of CCR2, injured Ccr2 Ϫ / Ϫ sciatic nerves demonstrate prolonged expression of neutrophil chemokines, a concomitant extended increase in the accumulation of neutrophils in the nerve, and elevated phagocytosis by neutrophils. Neutrophil depletion substantially inhibits myelin clearance after nerve injury in both male WT and Ccr2 Ϫ / Ϫ mice, highlighting a novel role for these cells in peripheral nerve degeneration that spans genotypes.

Spinal motor circuit synaptic plasticity after peripheral nerve injury depends on microglia activation and a CCR2 mechanism

“…Interestingly, there was a significant increase in blood neutrophils in CCR2 KOs. This compensatory increase in neutrophils has been reported before in CCR2 KOs (Saederup et al, 2010;Lindborg et al, 2017) and further confirms the KO phenotype and our detection methods.…”

Neutrophil–lymphocyte ratio and response to plasmapheresis in Guillain–Barré syndrome: a prospective observational study

“…Axon damage produces hundreds of times the normal amount of two chemokines CXCL1 and CXCL2 which attach to the surface of neutrophils and draw immune cells into injured tissues. The neutrophils engulf cellular debris tidying up the area for nerve repair [27].…”

Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL‐34, and SCF in amyotrophic lateral sclerosis

“…Following axonal loss, Schwann cell (SCs) become denervated and adopt an undifferentiated cell phenotype with profound transcriptional reprogramming and the upregulation of cytokines, chemokines and trophic factors (Jessen & Mirsky, ). In nerve injury, SCs can proliferate (Chang & Winkelstein, ), extend long processes across the gap to guide axonal growth (Gomez‐Sanchez et al, ) or adopt phagocytic features to remove myelin (Brosius Lutz et al, ; Lindborg, Mack, & Zigmond, ). Unlike Wallerian degeneration, peripheral nerve pathology in ALS is not solely a reparative condition because the inexorable failure in effective axonal growth leads to a chronic and progressive degenerative and inflammatory condition.…”

“…In turn, recruited macrophages become a source of secreted cytokine and trophic factor release, inducing a complex inflammatory cascade (Stratton et al, ; Tomlinson, Zygelyte, Grenier, Edwards, & Cheetham, ). Mast cells are also recruited (Esposito, De Santis, Monteforte, & Baccari, ), orchestrating complex vascular and immune cell responses, including the chemoattraction of phagocytic neutrophils that further contribute to myelin clearance (Lindborg et al, ). In comparison, ALS nerve pathology similarly involves reactive changes in SCs (Keller, Gravel, & Kriz, ) as well as the recruitment of monocytes, macrophages, mast cells, and neutrophils (Chiu et al, ; Trias et al, ; Van Dyke et al, ).Such immune cell infiltration of the peripheral motor pathways in ALS has been linked to both protective and deleterious effects on motor neuron degeneration and disease progression (Nardo et al, ).…”