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Significance Interactions between the immune system and nervous system regulate chronic pain. Cytokines are well-known immune-regulatory molecules that have activities beyond regulation of the immune system, including regulation of pain pathways. We identified that fusion of regulatory cytokines interleukin (IL)-4 and IL-10 into the fusion protein IL4–10 FP provides unexpected properties to inhibit pain by clustering the respective receptor chains of both cytokines in sensory neurons. IL4–10 FP promotes unique signaling pathways and gene-expression profiles that resolve chronic inflammatory pain. Thus IL4–10 FP is an immune biologic that effectively inhibits pain by activating pain-resolution pathways in sensory neurons through clustering of cytokine receptors. This unique effect discriminates IL4–10 FP from a combination therapy with individual regulatory cytokines.

Cytokine receptor clustering in sensory neurons with an engineered cytokine fusion protein triggers unique pain resolution pathways