{"doi":"10.1101/2025.04.22.650068","title":"Type I interferons enhance human dorsal root ganglion nociceptor excitability and induce TRPV1 sensitization","abstract":"Abstract Type I interferons (IFNs) are critical cytokines for antiviral defense and are linked to painful inflammatory diseases like rheumatoid arthritis and neuropathic pain in humans. Studies in rodent models demonstrate a direct action on sensory neurons in the dorsal root ganglion (DRG) to promote hyperexcitability but rodent behavioral results are conflicting with some reports of pro-nociceptive actions and others of anti-nociception. Given the role of type I IFNs in human disease, we sought to clarify the action of action of IFN-α and IFN-β on human DRG (hDRG) nociceptors. We found that IFN receptor subunits IFNAR1 and IFNAR2 are functionally expressed by these neurons and their engagement induces canonical STAT1 signaling and non-canonical MAPK activation as measured by increased phosphorylation of the cap-binding protein eIF4E by MNK1/2 kinases. Using patch clamp electrophysiology, Ca 2+ -imaging, and multi-electrode arrays we demonstrate that IFN-α and -β increase the excitability of hDRG neurons with short (30 min) and long-term (24-48 h) exposure and prolong the duration of capsaicin responses, an effect that is blocked by inhibition of MNK1/2 with eFT508, a specific inhibitor of these kinases. Our studies support the conclusion that type I IFNs are pronociceptive when they interact with hDRG nociceptors in the periphery.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":564916,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.955,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1002973,"name":"Keerthana Natarajan","orcid":"0009-0008-0818-5413","position":1,"is_corresponding":false},{"id":705828,"name":"Felipe Espinosa","orcid":null,"position":2,"is_corresponding":false},{"id":1166698,"name":"Rafael Granja-Vazquez","orcid":null,"position":3,"is_corresponding":false},{"id":1389100,"name":"Hemanth Mydugolam","orcid":"0009-0006-0877-0626","position":4,"is_corresponding":false},{"id":257966,"name":"Theodore J. Price","orcid":"0000-0002-6971-6221","position":5,"is_corresponding":false},{"id":279172,"name":"Úrzula Franco‐Enzástiga","orcid":"0000-0001-9450-5111","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T02:56:24.872312Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}