Mechanisms underlying macrophage action in nerve regeneration and degeneration

Project: Research projectResearch Project

Description

Peripheral nerve injury is common and occurs due to a variety of causes including trauma, diabetes, cancerchemotherapy, autoimmune reactions, and genetic disorders. Although peripheral neurons are capable ofregenerating, 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 acuteinjury due to their accumulation in the distal nerve where they phagocytize axonal debris and myelin therebycreating an environment through which axons can grow. In addition, macrophages secrete cytokines thattrigger growth factor synthesis in non-neuronal cells in the nerve. The absence of these actions has beenassumed 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 theaxotomized 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 mutantmouse strains, a knockout for the chemokine receptor CCR2 and the Wlds mice led to the hypothesis thatmacrophage 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 theDRG by the chemokine CCL2 trigger the expression of regeneration associated genes (RAGs) via thesecretion 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 thatCCL2-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 aneuron?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 butmonocyte infiltration into DRGs is blocked, these animals will allow us to determine whether macrophageaccumulation in DRGs is required for sensory nerve regeneration in vivo. Using these novel approaches, wewill 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.
StatusActive
Effective start/end date6/1/165/31/21

Funding

  • National Institutes of Health: $473,095.00

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Nerve Degeneration
Nerve Regeneration
Macrophages
Spinal Ganglia
Ganglia
Axons
Regeneration
Colony-Stimulating Factor Receptors
Cytokines
Wallerian Degeneration
Neurons
Axotomy
Peripheral Nerve Injuries
Inborn Genetic Diseases
Wild Animals
Macrophage Colony-Stimulating Factor
Microfluidics
Chemokine CCL2
Chemokine Receptors
Wounds and Injuries