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Review
. 2023 Mar 22;12(6):965.
doi: 10.3390/cells12060965.

The Similar and Distinct Roles of Satellite Glial Cells and Spinal Astrocytes in Neuropathic Pain

Aidan McGinnis  1 , Ru-Rong Ji  1   2   3
Affiliations
Review

The Similar and Distinct Roles of Satellite Glial Cells and Spinal Astrocytes in Neuropathic Pain

Aidan McGinnis et al. Cells. .

Abstract

Preclinical studies have identified glial cells as pivotal players in the genesis and maintenance of neuropathic pain after nerve injury associated with diabetes, chemotherapy, major surgeries, and virus infections. Satellite glial cells (SGCs) in the dorsal root and trigeminal ganglia of the peripheral nervous system (PNS) and astrocytes in the central nervous system (CNS) express similar molecular markers and are protective under physiological conditions. They also serve similar functions in the genesis and maintenance of neuropathic pain, downregulating some of their homeostatic functions and driving pro-inflammatory neuro-glial interactions in the PNS and CNS, i.e., "gliopathy". However, the role of SGCs in neuropathic pain is not simply as "peripheral astrocytes". We delineate how these peripheral and central glia participate in neuropathic pain by producing different mediators, engaging different parts of neurons, and becoming active at different stages following nerve injury. Finally, we highlight the recent findings that SGCs are enriched with proteins related to fatty acid metabolism and signaling such as Apo-E, FABP7, and LPAR1. Targeting SGCs and astrocytes may lead to novel therapeutics for the treatment of neuropathic pain.

Keywords: dorsal root ganglia; fatty acids; gliopathy; nerve injury; spinal cord.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Similar and distinct roles of SGCs and astrocytes in homeostasis and neuropathic pain conditions.
Figure 2
Figure 2
Schematic of SGC roles in homeostasis and neuropathic pain. (Left), SGCs surround a sensory neuron and maintain the homeostasis of the extracellular environment of the neuron. (Middle), enlarged box of left panel. (Right), peripheral nerve injury induces rapid reaction of SGCs in DRG and TG. These reactive SGCs drive neuropathic pain via secretion of neuromodulators, including ATP, cytokines (TNF-α, IL-1β), and chemokines. Nerve injury also results in downregulation of Kir4.1, leading to increases in extracellular K+ levels and neuronal excitability. Neuronal excitability is further enhanced by ATP, cytokines, and chemokine signaling via neuron–glial interactions. Additionally, upregulation of Cx43-mediated gap junction communication after nerve injury may further increase the release of cytokines and chemokines. Figure made with BioRender.
Figure 3
Figure 3
Single-cell analysis showing the expression of cellular marker genes in fibrous astrocytes, protoplasmic astrocytes, and SGCs. Gfap (encoding GFAP), S100b (encoding S100B), Sox9 (encoding Sox9), Aldh1l1 (encoding aldehyde dehydrogenase 1 family member L1), Gja1 (encoding connexin 43), Kcnj10 (encoding Kir4.1), Sparcl1 (encoding SPARCL1/high endothelial venule protein, hevin), Slc1a2 (encoding glutamine-transporter-1, GLT-1), Slc1a3 (encoding glutamine aspartate transporter 1, GLAST-1), and Glul (encoding glutamate-ammonia ligase/glutamine synthetase, GS). Single-cell RNAseq data were accessed from the mousebrain.org database [44] and are presented using Seurat v4.3.0 [53].
Figure 4
Figure 4
Schematic of astroglial roles in synaptic transmission and neuropathic pain. Nerve injury induces sustained reaction of spinal cord astrocytes. These reactive astrocytes drive neuropathic pain via secretion of neuromodulators, including adhesion molecules (hevin and TSP-4) and chemokines/cytokines. These astroglia-produced neuromodulators can increase the function of NMDA and AMPA receptors at both pre-synaptic and post-synaptic sites, leasing to enhanced excitatory synaptic transmission, central sensitization, and neuropathic pain. Astroglia-produced neuromodulators can further modulate inhibitory synaptic transmission, leading to disinhibition that further exacerbates neuropathic pain. Figure made with BioRender.
Figure 5
Figure 5
Distinct expression of lipid signaling molecules in SGCs and astrocytes. (A) RNAscope in situ hybridization shows Fabp7 (green, left) and Apoe (red, middle) mRNA expression in SGCs (labelled with yellow arrows) of mouse DRG. Right, counter staining of the same DRG section with Nissl (neuronal marker) and DAPI (nuclear marker). Note that Fabp7 and ApoE are not expressed in neurons. To generate Figure 5A, mice were transcardially perfused with 4% PFA, then DRG were further fixed overnight in 4% PFA, dehydrated in sucrose, frozen in OCT, sectioned onto slides, and stained via RNAscope according to the manufacturer’s instructions (Advanced Cell Diagnostics). Neurotrace/Nissl staining was performed thereafter (ThermoFisher). Imaging was performed using a Zeiss 880 inverted confocal microscope. (B) Single-cell analysis showing higher expression of Fabp7, ApoE, Hmgcs1 and 2, and Lpar1 in SGCs than astrocytes. Fabp7 (encoding fatty acid-binding protein 7, aka brain lipid-binding protein 1), Apoe (encoding apolipoprotein-E), Hmgcs1 (encoding HMG-CoA synthetase 1), and Lpari (encoding lysophosphatidic acid receptor 1). Single-cell RNAseq data were accessed from the mousebrain.org database [44] and presented using Seurat v4.3.0 [53].
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References

    1. O’Connor A.B. Neuropathic pain: Quality-of-life impact, costs and cost effectiveness of therapy. Pharmacoeconomics. 2009;27:95–112. doi: 10.2165/00019053-200927020-00002. - DOI - PubMed
    1. Raja S.N., Carr D.B., Cohen M., Finnerup N.B., Flor H., Gibson S., Keefe F.J., Mogil J.S., Ringkamp M., Sluka K.A., et al. The revised International Association for the Study of Pain definition of pain: Concepts, challenges, and compromises. Pain. 2020;161:1976–1982. doi: 10.1097/j.pain.0000000000001939. - DOI - PMC - PubMed
    1. Bates D., Schultheis B.C., Hanes M.C., Jolly S.M., Chakravarthy K.V., Deer T.R., Levy R.M., Hunter C.W. A Comprehensive Algorithm for Management of Neuropathic Pain. Pain Med. 2019;20:S2–S12. doi: 10.1093/pm/pnz075. - DOI - PMC - PubMed
    1. Volkow N.D., Collins F.S. The role of science in addressing the opioid crisis. N. Engl. J. Med. 2017;377:391–394. doi: 10.1056/NEJMsr1706626. - DOI - PubMed
    1. Milligan E.D., Watkins L.R. Pathological and protective roles of glia in chronic pain. Nat. Rev. Neurosci. 2009;10:23–36. doi: 10.1038/nrn2533. - DOI - PMC - PubMed

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