Implication of system x in Complete Freund's Adjuvant-induced peripheral inflammation and associated nociceptive sensitization.
(2025) Neuropharmacology — p. 110340 (2025)
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- Persistent inflammation leading to neuronal sensitization in pain pathways, are key features of chronic inflammatory pain. Alike macrophages in the periphery, glial cells exacerbate hypersensitivity by releasing proalgesic mediators in the central nervous system. Expressed by peripheral and central immune cells, the cystine-glutamate antiporter system x plays a significant role in inflammatory responses, but its involvement in chronic inflammatory pain remains underexplored. We herein investigated the contribution of this exchanger in nociceptive hypersensitivity triggered by a peripheral inflammatory insult. Complete Freund's adjuvant (CFA) was injected into the left hind paw of wild-type C57Bl/6 female mice, of xCT-deficient mice (specific subunit of system x) and of mice receiving the system x inhibitor sulfasalazine. Paw edema was measured over three weeks and pain-associated behaviors were evaluated. Additionally, pro-inflammatory cytokine levels were assessed in blood samples. CFA injection led to a persistent increase in paw edema and hypersensitivity to mechanical and thermal stimuli, which were less pronounced in xCT-deficient mice. This reduced sensitivity was accompanied by lower systemic pro-inflammatory cytokine levels in xCT-deficient mice. Accordingly, pharmacological inhibition of system x with sulfasalazine, either before or after pain induction, efficiently reduced the algesic and inflammatory responses to CFA in wild-type mice. Our findings reveal a critical role for system x in the pathophysiology of inflammatory pain. xCT deficiency reduces pain behaviors and peripheral inflammation, positioning system x as a promising therapeutic target for alleviating chronic inflammatory pain.
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Beckers, P., Charlier, M., Richter, L. A., Braconnier, P., Desmet, N., Massie, A., & Hermans, E. (2025). Implication of system x in Complete Freund’s Adjuvant-induced peripheral inflammation and associated nociceptive sensitization. Neuropharmacology, 110340. https://doi.org/10.1016/j.neuropharm.2025.110340 (Original work published 2025)