Abstract
Joint inflammatory diseases are debilitating and very painful conditions that still lack effective treatments. Recently, glial cells were shown to be crucial for the development and maintenance of chronic pain, constituting novel targets for therapeutic approaches. At the periphery, the satellite glial cells (SGCs) that surround the cell bodies of primary afferents neurons in the dorsal root ganglia (DRG) display hypertrophy, proliferation, and activation following injury and/or inflammation. It has been suggested that the expression of neuronal injury factors might initially trigger these SGCs-related events. We then aimed at evaluating if SGCs are involved in the establishment/maintenance of articular inflammatory pain, by using the monoarthritis (MA) model, and if the neuronal injury marker activating transcriptional factor 3 (ATF3) is associated with these SGCs' reactive changes. Western Blot (WB) analysis of the glial fibrillary acidic protein (GFAP) expression was performed in L4-L5 DRGs from control non-inflamed rats and MA animals at different time-points of disease (4, 7, and 14d, induced by complete Freund's adjuvant injection into the left hind paw ankle joint). Data indicate that SGCs activation is occurring in MA animals, particularly after day 7 of disease evolution. Additionally, double-immunostaining for ATF3 and GFAP in L5 DRG sections shows that SGCs's activation significantly increases around stressed neurons at 7d of disease, when compared with control animals. The specific labelling of GFAP in SGCs rather than in other cell types was also confirmed by immunohistochemical labeling. Finally, BrdU incorporation indicates that proliferation of SGCs is also significantly increased after 7 days of MA. Data indicate that SGCs play an important role in the mechanisms of articular inflammation, with 7 days of disease being a critical time-point in the MA model, and suggest that ATF3 might be involved in SGCs' reactive changes such as activation.
Highlights
Inflammation of the joint is characterized, among others, by debilitating mechanical hyperalgesia and persistent pain at rest
satellite glial cells (SGCs) are activated during MA MA was successfully and homogenously induced in all the animals injected with Complete Freund’s Adjuvant (CFA), as they were all showing severe inflammatory symptoms with swelling, redness and avoidance to put weight over the inflamed paw at each time-point of disease
We show for the first time in the CFA-induced monoarthritis model of chronic joint inflammation that SGCs are activated and proliferate, with a specific temporal profile
Summary
Inflammation of the joint is characterized, among others, by debilitating mechanical hyperalgesia and persistent pain at rest. It is one of the major causes of chronic pain and a relevant clinical problem in need of better therapeutic approaches. In the peripheral nervous system (PNS), pain mechanisms involve sensitization of primary afferents neurons whose cell bodies are located in the dorsal root ganglia (DRG). In the DRGs, the cell bodies of these primary afferents are anatomically surrounded by satellite glial cells (SGCs) forming distinct functional units [4]. In the PNS, GFAP expression is commonly used as a marker of SGCs activation [4,5,6]. SGCs’ properties and functions have not yet been fully studied, it is clear that these cells take an important part in the ‘‘intercellular communication’’ [3] with the neuronal cells they are in contact with
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