# Neuroinflammation in Wallerian Degeneration and Regeneration: Neutrophils Play a Primary Role as Phagocytes

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $500,193

## Abstract

Understanding the process of neural degeneration is important in order to understand the responses of the
nervous system to injury and disease. A common model used in such studies is the distal segment of the sciatic
nerve after nerve transection or crush. Following such a lesion, Wallerian degeneration occurs in which the distal
segment of the nerve fragments and degenerates, and the resulting axonal and myelin debris are cleared away.
Interestingly, while this process occurs rapidly in the peripheral nervous system (PNS), it is extremely slow in
the central nervous system (CNS), and, partly because of this, regeneration is generally ineffective in the brain
and spinal cord. It is widely believed that inflammatory macrophages (mφs) derived from blood-borne monocytes
are required for the phagocytosis of axonal and myelin debris. Immune cells enter injured tissue in response to
chemotactic cytokines or chemokines. A major population of monocytes infiltrates into the distal nerve after
axotomy in response to the chemokine CCL2, which acts on monocytes via the chemokine receptor CCR2. In
mice in which the gene for CCR2 is knocked out, CCR2+ monocytes do not enter the nerve. It was, therefore,
very surprising when we found that the clearance of both myelin and axonal protein is normal in Ccr2 knockout
mice. We subsequently found that an important reason for the normal clearance appears to be phagocytosis by
neutrophils, an immune cell not previously implicated in Wallerian degeneration. In fact, although neutrophil
actions in the CNS are beginning to be examined, for example in models of multiple sclerosis, there are almost
no studies on their actions in the PNS. Our preliminary evidence using the neutrophil-depleting antibody anti-
Ly6G suggests, but does not prove, that neutrophils directly phagocytose and metabolize myelin. We will
examine this hypothesis by examining the clearance of myelin proteins by western blotting before and after
neutrophil depletion and by co-labeling tissue with Oil Red O, a stain for myelin metabolites, and with cell type
specific neutrophils antibodies. We have shown that after axotomy two neutrophil attracting chemokines are
induced in the sciatic nerve, CXCL1 and CXCL2. To determine whether these chemokines and their receptor,
CXCR2, are involved in neutrophil infiltration into the nerve, we will use neutralizing antibodies, pharmacological
antagonists, and knockout mice. We will investigate also whether the involvement of neutrophils in Wallerian
degeneration is important for subsequent regeneration. “Wallerian-like” degeneration occurs in several
demyelinating neuropathies, and we will examine whether neutrophils play a role in this phenomenon. We will
use a mouse model for Guillain Barré syndrome based on our recent finding that neutrophils enter into the sciatic
nerve in this model. Following up on our unexpected findings of normal clearance of myelin in Ccr2 knockout
mice, our experiments will examine the role of...

## Key facts

- **NIH application ID:** 10219366
- **Project number:** 5R01NS114891-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** RICHARD E ZIGMOND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $500,193
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219366

## Citation

> US National Institutes of Health, RePORTER application 10219366, Neuroinflammation in Wallerian Degeneration and Regeneration: Neutrophils Play a Primary Role as Phagocytes (5R01NS114891-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10219366. Licensed CC0.

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