Journal Article

Rheumatoid arthritis synovial fluid induces JAK-dependent intracellular activation of human sensory neurons

Lock, Amy, Kamajaya, Louisa Janice, Ross, Rosie, Denk, Franziska, John, Susan, Zebochin, Irene, Li, Yuening, Ryan, Sarah, Gray, Elizabeth H., Brüstle, Oliver, Röderer, Pascal, Taams, Leonie S., Fedele, Laura, Marrow, Rebecca J.

2025

Overview

JAK inhibitors (JAKi) are widely used antiinflammatory drugs. Recent data suggest that JAKi have superior effects on pain reduction in rheumatoid arthritis (RA). However, the underlying mechanisms for this observation are not fully understood. We investigated whether JAKi can act directly on human sensory neurons. We analyzed RNA-seq datasets of sensory neurons and found that they expressed JAK1 and STAT3. Addition of cell-free RA synovial fluid to human induced pluripotent stem cell-derived (iPSC-derived) sensory neurons led to phosphorylation of STAT3 (pSTAT3), which was completely blocked by the JAKi tofacitinib. Compared with paired serum, RA synovial fluid was enriched for the STAT3 signalling cytokines IL-6, IL-11, LIF, IFN-α, and IFN-β, with their requisite receptors present in peripheral nerves postmortem. Accordingly, these recombinant cytokines induced pSTAT3 in iPSC-derived sensory neurons. Furthermore, IL-6 + sIL-6R and LIF upregulated expression of pain-relevant genes with STAT3-binding sites, an effect that was blocked by tofacitinib. LIF also induced neuronal sensitization, highlighting this molecule as a putative pain mediator. Finally, over time, tofacitinib reduced the firing rate of sensory neurons stimulated with RA synovial fluid. Together, these data indicate that JAKi can act directly on human sensory neurons, providing a potential mechanistic explanation for their suggested superior analgesic properties.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Analgesics / Anti-inflammatory agents / Arthritis, Rheumatoid - drug therapy / Arthritis, Rheumatoid - metabolism / Cytokines / Cytokines - metabolism / Female / Firing rate / Flow cytometry / Gene expression / Humans / Immunology / Induced Pluripotent Stem Cells - metabolism / Inflammation / Interleukin 6 / Janus kinase / Janus Kinase 1 - metabolism / Janus Kinase Inhibitors - pharmacology / Janus Kinases - metabolism / Kinases / Male / Nervous system / Neurons / Neuroscience / Pain / Peripheral nerves / Phosphorylation / Phosphorylation - drug effects / Piperidines - pharmacology / Pluripotency / Pyrimidines - pharmacology / Rheumatoid arthritis / Sensory neurons / Sensory Receptor Cells - drug effects / Sensory Receptor Cells - metabolism / Signal Transduction - drug effects / Stat3 protein / STAT3 Transcription Factor - metabolism / Stem cells / Synovial fluid / Synovial Fluid - metabolism / α-Interferon / β-Interferon