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Upadacitinib regulates pain-related pathways and BDNF expression in human monocyte-derived microglial-like cells
M Vomero1, E Corberi2, O Berardicurti3
1Clinical unit of Immunorheumatology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; Department of Sciences and Technologies for Sustainable Development and One Health, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Rome, Italy.
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.
Insights
Upadacitinib (upa), a JAK1 inhibitor, reduces pain by downregulating brain-derived neurotrophic factor (BDNF) in microglia-like cells. This treatment promotes an anti-nociceptive profile, easing chronic pain in inflammatory conditions.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Chronic pain persists in inflammatory arthritis despite reduced joint inflammation.
- Microglial cells contribute to neuroinflammation and pain via cytokines like IL-1β and BDNF.
- Upadacitinib (upa), a JAK1 inhibitor, shows efficacy in reducing disease activity and pain, but its pain-relief mechanisms need clarification.
Purpose of the Study:
- To investigate how upa influences pain and neuroinflammation-related molecules in a human microglia-like cell model.
- Specifically, to determine upa's effect on BDNF production and its underlying mechanisms.
Main Methods:
- Utilized a pro-inflammatory human monocyte-derived microglia-like (M1-MDMi) cell model.
- Applied in vitro upadacitinib (upa) treatment to inhibit JAK1.
- Performed transcriptomic analysis to assess gene expression changes.
Main Results:
- Upadacitinib treatment downregulated BDNF expression and secretion.
- This downregulation was mediated by the modulation of the P2X4 receptor.
- Transcriptomic analysis revealed that upa induced an anti-nociceptive profile by reducing neuroinflammatory and pain-related pathways.
Conclusions:
- JAK1 inhibition by upadacitinib effectively reduces BDNF production in microglia-like cells.
- Upadacitinib modulates the P2X4 receptor, impacting central pain perception mechanisms.
- Upadacitinib demonstrates potential as a therapeutic agent for chronic pain by promoting an anti-nociceptive state.
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