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Mechanisms underlying macrophage action in nerve regeneration and degeneration

巨噬细胞在神经再生和变性中作用的机制

基本信息

批准号：
9531755
负责人：
RICHARD E ZIGMOND
金额：
$ 8.72万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9531755
关键词：
AVIL gene Acute Affect American Animals Autoimmune Process Axon Axotomy CCL2 gene Cells Chemotherapy-Oncologic Procedure Clinical Conditioned Culture Media Diabetes Mellitus Distal Environment Evaluation Ganglia Gene Expression Generations Genes Genetic Growth Growth Factor HIV Hereditary Disease In Situ Hybridization Infiltration Injury Intervention Knock-out LIF gene Lesion Macrophage Colony-Stimulating Factor Receptor Measures Mediating Medical Microfluidics Modeling Molecular Mus Mutant Strains Mice Myelin Natural regeneration Nerve Nerve Degeneration Nerve Regeneration Neurites Neuroglia Neuroimmune Neurons Peripheral Peripheral Nervous System Peripheral Nervous System Diseases Peripheral nerve injury Phagocytes Phenotype Process Reaction Recovery Schwann Cells Signal Pathway Site Spinal Ganglia Surgical incisions Testing Thinking Trauma Uncertainty Virus Wallerian Degeneration Work afferent nerve axon growth cell type chemokine chemokine receptor chemotherapy conditioning cytokine design effective therapy ganglion cell hereditary neuropathy improved in vivo in vivo regeneration inhibitor/antagonist injured insight knock-down macrophage monocyte monocyte chemoattractant protein 1 receptor neurite growth neuroinflammation neuronal cell body novel strategies peripheral nerve regeneration permissiveness regenerative response sciatic nerve transcriptome sequencing

项目摘要

Peripheral nerve injury is common and occurs due to a variety of causes including trauma, diabetes, cancer chemotherapy, autoimmune reactions, and genetic disorders. Although peripheral neurons are capable of regenerating, this process is generally incomplete. It is therefore crucial to determine ways in which regener- ation can be enhanced. Macrophages are thought to promote peripheral nerve regeneration after an acute injury due to their accumulation in the distal nerve where they phagocytize axonal debris and myelin thereby creating an environment through which axons can grow. In addition, macrophages secrete cytokines that trigger growth factor synthesis in non-neuronal cells in the nerve. The absence of these actions has been assumed to be the basis for the slow regeneration that occurs in the slowly degenerating Wlds mouse. How- ever, it has been known for 20 years. In part due to our studies. that there is a second, distinct, site of mac- rophage accumulation after injury, namely, peripheral ganglia such as dorsal root ganglia (DRGs) where the axotomized cell bodies reside. What has remained unknown is what function these macrophages subserve. Recent studies from our lab represent a major advance in answering this question. Work with two mutant mouse strains, a knockout for the chemokine receptor CCR2 and the Wlds mice led to the hypothesis that macrophage accumulation in ganglia is required for the occurrence of the conditioning lesion (CL) response, the response in which neurite outgrowth after a lesion is increased as a consequence of an earlier condition- ing lesion. This application is designed to test the following overall model: macrophages brought into the DRG by the chemokine CCL2 trigger the expression of regeneration associated genes (RAGs) via the secretion of cytokines around axotomized cell bodies and this promotes the CL response and regen- eration in addition to any effects macrophages have on the distal nerve. To establish beyond doubt that CCL2-dependent macrophage accumulation and the CCL2-dependent CL response are causally related, we will use an inhibitor of colony stimulating factor 1 receptors to deplete circulating monocytes. To deter- mine whether macrophages act directly on neuronal cell bodies, we will use microfluidic chambers in which a neuron’s cell body and axon can be separated. Gene expression using RNAseq will be compared after ax- otomy in CCRs -/- and wild type animals to determine which axotomy-induced genes are dependent on mac- rophage accumulation. Since we have shown that Wallerian degeneration is normal in CCR2 -/- mice but monocyte infiltration into DRGs is blocked, these animals will allow us to determine whether macrophage accumulation in DRGs is required for sensory nerve regeneration in vivo. Using these novel approaches, we will examine the mechanisms underlying the relationship between macrophage accumulation near axoto- mized cell bodies and axonal growth. Emphasizing ganglia, unexplored sites of neuroinflammation, repre- sents a paradigm shift from the traditional view that focuses on macrophage effects on the distal nerve.

周围神经损伤是一种常见的疾病，其原因包括外伤、糖尿病、癌症等