Abstract
BackgroundThe autoimmune disease rheumatoid arthritis (RA) affects approximately 1% of the global population. RA is characterized with chronic joint inflammation and often associated with chronic pain. The imbalance of pro-inflammatory and anti-inflammatory macrophages is a feature of RA progression. Glial cells affecting neuronal sensitivity at both peripheral and central levels may also be important for RA progression and associated pain. Genetic variants in the T cell death-associated gene 8 (TDAG8) locus are found to associate with spondyloarthritis. TDAG8 was also found involved in RA disease progression and associated hyperalgesia in the RA mouse model. However, its modulation in RA remains unclear.MethodsTo address this question, we intra-articularly injected complete Freund’s adjuvant (CFA) into TDAG8+/+, TDAG8−/− or wild-type mice, followed by pain behavioral tests. Joints and dorsal root ganglia were taken, sectioned, and stained with antibodies to observe the number of immune cells, macrophages, and satellite glial cells (SGCs). For compound treatments, compounds were intraperitoneally or orally administered weekly for 9 consecutive weeks after CFA injection.ResultsWe demonstrated that TDAG8 deletion slightly reduced RA pain in the early phase but dramatically attenuated RA progression and pain in the chronic phase (> 7 weeks). TDAG8 deletion inhibited an increase in SGC number and inhibition of SGC function attenuated chronic phase of RA pain, so TDAG8 could regulate SGC number to control chronic pain. TDAG8 deletion also reduced M1 pro-inflammatory macrophage number at 12 weeks, contributing to the attenuation of chronic RA pain. Such results were further confirmed by using salicylanilide derivatives, CCL-2d or LCC-09, to suppress TDAG8 expression and function.ConclusionsThis study demonstrates that TDAG8 deletion reduced SGC and M1 macrophage number to relieve RA disease severity and associated chronic pain. M1 macrophages are critical for the development and maintenance of RA disease and pain, but glial activation is also required for the chronic phase of RA pain.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease and characterized with chronic joint inflammation
T cell death-associated gene 8 (TDAG8) gene deficiency reduced satellite glial cell (SGC) number, and SGC inhibition attenuated the chronic phase of rheumatoid arthritis (RA) pain, which suggests that TDAG8 deficiency relieved the late phase of RA pain by regulating SGCs in part
To determine whether the number of SGCs was increased in our RA mice, dorsal root ganglia (DRG) from RA mice were immunostained for anti-glial fibrillary acidic protein (GFAP)
Summary
Rheumatoid arthritis (RA) is an autoimmune disease and characterized with chronic joint inflammation. In RA, the neurophysiological mechanisms underlying pain remain unclear. Experimental animal models of inflammatory arthritis suggest that changes in neuronal sensitivity at both peripheral and central levels may be important [4, 5]. The acute phase of pain could be associated with acute joint inflammation, but the chronic phase could be linked to inflammatory components of neuron–immune interactions and non-inflammatory components such as neuron–glia interactions or central mechanisms [6, 7]. Glial cells affecting neuronal sensitivity at both peripheral and central levels may be important for RA progression and associated pain. TDAG8 was found involved in RA disease progression and associated hyperalgesia in the RA mouse model. Compounds were intraperitoneally or orally administered weekly for 9 consecutive weeks after CFA injection
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