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Review
. 2019 Feb:173:102-121.
doi: 10.1016/j.pneurobio.2018.12.001. Epub 2018 Dec 21.

Macrophage biology in the peripheral nervous system after injury

Richard E Zigmond  1 , Franklin D Echevarria  2
Affiliations
Review

Macrophage biology in the peripheral nervous system after injury

Richard E Zigmond et al. Prog Neurobiol. 2019 Feb.

Abstract

Neuroinflammation has positive and negative effects. This review focuses on the roles of macrophage in the PNS. Transection of PNS axons leads to degeneration and clearance of the distal nerve and to changes in the region of the axotomized cell bodies. In both locations, resident and infiltrating macrophages are found. Macrophages enter these areas in response to expression of the chemokine CCL2 acting on the macrophage receptor CCR2. In the distal nerve, macrophages and other phagocytes are involved in clearance of axonal debris, which removes molecules that inhibit nerve regeneration. In the cell body region, macrophage trigger the conditioning lesion response, a process in which neurons increase their regeneration after a prior lesion. In mice in which the genes for CCL2 or CCR2 are deleted, neither macrophage infiltration nor the conditioning lesion response occurs in dorsal root ganglia (DRG). Macrophages exist in different phenotypes depending on their environment. These phenotypes have different effects on axonal clearance and neurite outgrowth. The mechanism by which macrophages affect neuronal cell bodies is still under study. Overexpression of CCL2 in DRG in uninjured animals leads to macrophage accumulation in the ganglia and to an increase in the growth potential of DRG neurons. This increased growth requires activation of neuronal STAT3. In contrast, in acute demyelinating neuropathies, macrophages are involved in stripping myelin from peripheral axons. The molecular mechanisms that trigger macrophage action after trauma and in autoimmune disease are receiving increased attention and should lead to avenues to promote regeneration and protect axonal integrity.

Keywords: Axotomy; Chemokine; Conditioning lesion; Dorsal root ganglion; Macrophage; Neuroinflammation; Wallerian degeneration.

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Figures

Fig. 1.
Fig. 1.
A diagram of a hypothetical peripheral neuron following axonal transection or crush showing the two sites of macrophage accumulation.. The lower part of the figure shows the degeneration of the distal axonal segment, the trans-differentiation of Schwann cells, the secretion by the Schwann cells of the chemokine CCL2, and the attraction of macrophages to the distal degenerating segment. This is the classical view of macrophage accumulation after axotomy. The upper part of the figure shows that macrophages also accumulate around the axotomized neuronal cell body and these neurons themselves secrete the chemokine CCL2 following axotomy.
Fig. 2.
Fig. 2.
Seven days after unilateral transection of the sciatic nerve, myelin in the distal nerve segment was stained with luxol fast blue. (a) Ipsilateral nerves from wild type and Ccr2 knockout mice retained about 20% of the myelin reactivity seen in contralateral control nerves. On the other hand, the ipsilateral distal nerves from Wlds mice retained about 80% of the myelin seen in contralateral controls. Micrographs from sections of the ipsilateral (e-g) and contralateral (b-d) from wild type (WT) (b,e), Wlds (c,f) and Ccr2 knockout (d,g). *p<0.05, **p<0.001. Scale bar, 20 µm. From Niemi et al., 2013.
Fig. 3.
Fig. 3.
Seven days after sciatic nerve transection, a conditioning lesion effect was seen in explanted DRGs from wild type but not from Ccr2 mice measured at 24 (a) and 48 (b) hours. Phase micrographs are shown of DRG explants from wild type (WT) (c) and Ccr2 (d) ater 48 hours in culture. Arrows point to endings of individual neurites. *p<0.05, **p<0.001, Scale bars, 100 µm. From Niemi et al., 2013.
Fig. 4.
Fig. 4.
CCL2 overexpression causes a conditioning lesion-like increase in neurite outgrowth by DRG neurons from mice that received 3 weeks earlier an injection of AAV5-CCL2. Neurite outgrowth was measured in explant (A-C) and in cell (D-F) cultures. In contrast, if CCL2 (200 ng/ml) was added directly to such cultures, no effect on neurite outgrowth was seen (G-L). *p<0.05, **p<0.001. Scale bar, 100 µm. From Niemi et al., 2016.
Fig. 5.
Fig. 5.
A. Diagram showing the polarization of macrophages in vitro by LPS and IFNγ to an M1-like phenotype and by IL-4 and IL-13 to an M2-like phenotype. The color spectrum between the two subtypes indicates the spectrum of macrophage phenotypes that are thought to exist in vivo. M1 macrophages express nitric oxide synthase (iNOS) and secrete TNFα, IL-6, reactive oxygen species (ROS), IL-1β, NO (nitric oxide), and matrix metalloproteinases (MMPs). M2 macrophages express arginase and secrete IL10, TGF-β, and extracellular matrix molecules (ECM). B. Questions remain as to the exact function of M1 (pink)- and M2 (blue)-like macrophages on the axotomized neuronal cell bodies and the distal nerve segment.
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