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

华勒变性和再生中的神经炎症：中性粒细胞作为吞噬细胞发挥主要作用

基本信息

批准号：
10219366
负责人：
RICHARD E ZIGMOND
金额：
$ 50.02万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10219366
关键词：
Acute Animal Model Anti-Inflammatory Agents Antibodies Attention Axon Axotomy B-Lymphocytes Blood Brain CCL2 gene CXCL1 gene CXCL2 gene Cells Demyelinating Diseases Demyelinations Disease Disease Progression Distal Electrons Electrophysiology (science)Enzyme-Linked Immunosorbent Assay Excision Experimental Autoimmune Neuritis Ganglia Genes Growth Guillain Barré Syndrome IL8RB gene Immune In Situ Hybridization Inflammatory Injury Interleukin-8B Receptor Knock-out Knockout Mice Label Lesion Measures Modeling Multiple Sclerosis Mus Myelin Myelin Proteins Natural regeneration Nerve Nerve Crush Nerve Degeneration Nerve Regeneration Nervous system structure Neural Conduction Neuraxis Neuroglia Neuroimmune Neurons Neuropathy Neutrophil Infiltration Neutrophilic Infiltrate Oils Pathologic Pathology Peripheral Peripheral Nervous System Peripheral Nervous System Diseases Phagocytes Phagocytosis Pharmacology Phenotype Play Population Process Proteins Public Health Recovery of Function Reporting Role Schwann Cells Spinal Cord Stains T-Lymphocyte Techniques Time Tissues Tolonium chloride Trauma Wallerian Degeneration Western Blotting Wild Type Mouse base cell type chemokine chemokine receptor experimental study improved indexing injured macrophage monocyte monocyte chemoattractant protein 1 receptor mouse model nerve transection nervous system disorder neuroinflammation neutralizing antibody neutrophil novel receptor regenerative relating to nervous system response sciatic nerve

项目摘要

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 neutrophils in Wallerian degeneration and in a demyelinating disease. Given the known importance of Wallerian degeneration for nerve regeneration due to the removal of myelin proteins, our studies will suggest ways of improving regeneration in the PNS and perhaps in the CNS.

了解神经退行性变的过程对于理解细胞的反应是很重要的