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

Overview

1. Department of Medical Biochemistry and Biophysics, Division of Molecular Neurobiology, Karolinska Institutet, Stockholm, Sweden
2. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
3. Department of Medical Biochemistry and Biophysics, Division of Immunology, Karolinska Institutet, Stockholm, Sweden
4. Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience, Linköping University, Linköping, Sweden

Abstract

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

No file of the authors' code could be read here: it is described below, and read at its source.

Code availability

The code and analysis steps for the intercellular ligand–receptor analysis are accessible as a Jupyter Notebook on https://sccamel.readthedocs.io/. Previously published code and software used for this study are cited and described in the Methods.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE218634, at NCBI GEO; found in “Data availability”

Data availability

The RNA-seq datasets generated and analyzed during the study have been deposited in the Gene Expression Omnibus (GEO) repository under a SuperSeries accession number GSE218634 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE218634). Source data are provided with this paper.

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 15 authors, 3 keywords, 13 MeSH terms, 3 funders, 71 references.

Cite

This paper

Su, J., Zhang, M.-D., Kupari, J., Kwak, D., Picton, L., Xu, B., do Nascimento, L. F., Hu, Y., Gonzalez, A., Usoskin, D., Xu, Z., Szczot, M., El Manira, A., Holmdahl, R., & Ernfors, P. (2026). Persistent interferon signaling causes sensory neuron plasticity and pain before and during arthritis. Nature neuroscience, 29(5), 1095-1108. https://doi.org/10.1038/s41593-026-02234-y

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