Satellite Glial Cells in Human Disease

Abstract

Satellite glial cells (SGCs) are the main type of glial cells in sensory ganglia. Animal studies have shown that these cells play essential roles in both normal and disease states. In a large number of pain models, SGCs were activated and contributed to the pain behavior. Much less is known about SGCs in humans, but there is emerging recognition that SGCs in humans are altered in a variety of clinical states. The available data show that human SGCs share some essential features with SGCs in rodents, but many differences do exist. SGCs in DRG from patients suffering from common painful diseases, such as rheumatoid arthritis and fibromyalgia, may contribute to the pain phenotype. It was found that immunoglobulins G (IgG) from fibromyalgia patients can induce pain-like behavior in mice. Moreover, these IgGs bind preferentially to SGCs and activate them, which can sensitize the sensory neurons, causing nociception. In other human diseases, the evidence is not as direct as in fibromyalgia, but it has been found that an antibody from a patient with rheumatoid arthritis binds to mouse SGCs, which leads to the release of pronociceptive factors from them. Herpes zoster is another painful disease, and it appears that the zoster virus resides in SGCs, which acquire an abnormal morphology and may participate in the infection and pain generation. More work needs to be undertaken on SGCs in humans, and this review points to several promising avenues for better understanding disease mechanisms and developing effective pain therapies.

Keywords: autoimmune diseases; dorsal root ganglion; fibromyalgia; herpes; rheumatoid arthritis; satellite glial cells; sensory neuron; trigeminal ganglion.

Figure 1

The neuron–SGC unit. A low power electron micrograph showing SGCs (marked red) surrounding a neuronal soma (N) in mouse trigeminal ganglion. Three nuclei of SGCs are marked with asterisks (*). BV, blood vessel; Ax, axon.

Figure 2

Nodule of Nageotte in human DRG (patient with ganglionitis). The black arrow points at a cluster of SGCs that constitute a nodule. The white arrows indicate normal neurons, which are surrounded by SGCs (their nuclei are stained blue). Reproduced with permission from Rees, J. Neurol. Neurosurg. Psychiatry [41], published by BMJ, 2004.

Figure 3

SGCs in VZV infection. (A) Micrograph of a neuron (1) labeled red for RT97 (mechanoreceptor marker) surrounded by abnormal onion-like layers of SGCs (labeled green for the VZV protein IE63). (B) Diagram depicting two possible modes by which sensory neurons can be infected by VZV. (1) Primary VZV infection is initiated in respiratory epithelial cells, followed by transfer to T cells in lymphoid tissue. The virus is represented as red dots. (2) Infected T cells enter the circulation. (3) T cells carry the virus to the skin. (4) From the skin, T cells reach DRG neurons by retrograde axonal transport. (5) The T cells also reach the DRG directly. Both pathways promote infection of DRG cells. (6) VZV gains access to both nociceptive (small, orange) and mechanoreceptive (large, green) neuronal somata by either route. Replication occurs only in nociceptive neurons. If replication in neurons is uncontrolled, infection of SGC facilitates spread to neighboring neuron–SGC units. (7) Over time, VZV infection in SGC contributes to neuronal death, mostly of mechanoreceptors, which presumably are more dependent on SGCs support than nociceptors. This leads to the formation of nodules of Nageotte. Reprinted from Zerboni and Arvin [50] under Creative Commons Attribution (CC-BY) license from PLOS Pathog.

Figure 4

Human DRG immunostained for ACE-2. The arrows point at cells that might be SGCs. Scale bar, 20 µm. Reprinted from [64] under Creative Commons Attribution (CC-BY) license, Pain Rep., LLW, 2021.

Figure 5

Neuron–SGC interactions in RA. (A) Sections of human DRG showing immunostaining for LPA1, the SGC marker glutamine synthetase (GS), and the nuclear dye DAPI (blue). The combined image (right) shows clear colocalization of the LPA receptor LPA1 and GS in SGCs. Scale bar, 50 µm. (B) Schematic of lysophosphatidic acid (LPA) signaling in collagen antibody-induced arthritis (CAIA). In the CAIA model, autotaxin (ATX) is elevated in DRG neurons, possibly in response to sensitizing stimuli such as joint inflammation and immune complex activation of nociceptors. ATX increases the levels of LPA, which activates SGCs that express LPA1, leading to SGC activation. Activated SGCs produce increased levels of pronociceptive cytokines and NGF, which can then act on the corresponding receptors in the neurons. This further promotes nociceptor excitability, leading to the development of chronic pain. Reprinted under Creative Commons Attribution (CC-BY) license from Su et al. [80] Brain Behav. Immun., Elsevier, 2022.

Figure 6

Satellite glial cells and neurons are altered in Friedreich ataxia (FA). (A) Section of DRG from a normal person labeled for the protein laminin. Note the thin SGC envelope around the neuron. (B) Section of DRG from an FA patient showing abnormal onion-like layers and projections outside the neuron–SGC unit. From Koeppen et al. [35]. Reproduced with permission from Reprinted under Creative Commons Attribution (CC-BY) license.

Figure 7

Immunostaining for glial fibrillary acidic protein (GFAP) of human DRG. (A) Normal control. (B) FA patients. Both images show positive staining for GFAP, but the total amount of the protein is considerably greater in the DRG from the FAS patient. For further details, see Koeppen et al. [35]. Courtesy of Prof. A. Koeppen, Veterans Affairs Medical Center, Albany, NY, USA.