Upadacitinib regulates pain-related pathways and BDNF expression in human monocyte-derived microglial-like cells

Abstract

Chronic pain is one of the most critical symptoms reported by patients with inflammatory arthritis, and even when joint inflammation improves, disabling residual pain may persist in a significant number of patients. Microglial cells, by producing different pro-inflammatory cytokines and pain-related molecules, including IL-1β and BDNF, are involved in neuroinflammation process. Treatment with Upadacitinib (upa), a JAK1 inhibitor, has been shown to be effective in improving disease activity and quickly relieving pain; however, the biological mechanisms underlying its efficacy against pain perception still require further investigation. This study aims to investigate whether and how upa may influence the production of pain and neuroinflammation-related molecules in pro-inflammatory human monocyte-derived microglia-like (M1-MDMi) model, specifically regarding BDNF. JAK1 inhibition by in vitro upa treatment downregulated BDNF expression and secretion by the modulation of P2X4 receptor, thus affecting a central mechanism involved in pain perception. Moreover, transcriptomic analysis showed that upa promoted an anti-nociceptive profile in the human glial model, by reducing the expression of neuroinflammatory, acute, and chronic pain-related pathways.