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<p>Although inflammatory processes in rheumatoid arthritis have been described, mechanisms driving pain are poorly defined. Here, we used a multitude of approaches to uncover the neural basis and causes of inflammatory pain. We show in mice with cartilage autoantibody-induced arthritis that early immune activation and a cytokine storm were mainly driven by vascular cells and monocytes/macrophages in the dorsal root ganglion. However, persistently elevated interferons and receptor activation of the MNK1/MNK2–eIF4E signaling pathway at all disease phases caused sensory–motor dysfunction and pain by inducing hyperexcitability and sensitization of a GFRA3<sup>+</sup> C-fiber subtype of joint-innervating sensory neurons. Signaling pathway inhibition in vivo reversed pain and restored limb function. Like mice, human sensory neurons expressed interferon receptors, and type 1 interferons and signaling were increased only in individuals with painful rheumatoid arthritis. The finding that joint pain before and during arthritis is caused by a defined cytokine and signaling pathway holds promise for targeted therapies for pain relief in arthritis.</p>

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Persistent interferon signaling causes sensory neuron plasticity and pain before and during arthritis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月10日

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  • Jie Su,
  • Ming-Dong Zhang,
  • Jussi Kupari,
  • Dongoh Kwak,
  • Laurence Picton,
  • Bingze Xu,
  • Leandro Flores do Nascimento,
  • Yizhou Hu,
  • Alejandro Gonzalez,
  • Dmitry Usoskin,
  • Zhongwei Xu,
  • Marcin Szczot,
  • Abdeljabbar El Manira,
  • Rikard Holmdahl,
  • Patrik Ernfors

摘要

Although inflammatory processes in rheumatoid arthritis have been described, mechanisms driving pain are poorly defined. Here, we used a multitude of approaches to uncover the neural basis and causes of inflammatory pain. We show in mice with cartilage autoantibody-induced arthritis that early immune activation and a cytokine storm were mainly driven by vascular cells and monocytes/macrophages in the dorsal root ganglion. However, persistently elevated interferons and receptor activation of the MNK1/MNK2–eIF4E signaling pathway at all disease phases caused sensory–motor dysfunction and pain by inducing hyperexcitability and sensitization of a GFRA3+ C-fiber subtype of joint-innervating sensory neurons. Signaling pathway inhibition in vivo reversed pain and restored limb function. Like mice, human sensory neurons expressed interferon receptors, and type 1 interferons and signaling were increased only in individuals with painful rheumatoid arthritis. The finding that joint pain before and during arthritis is caused by a defined cytokine and signaling pathway holds promise for targeted therapies for pain relief in arthritis.