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

Autor:	Prado J; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, The Netherlands., Westerink RHS; Neurotoxicology Research Group, Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands., Popov-Celeketic J; Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, The Netherlands., Steen-Louws C; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, The Netherlands., Pandit A; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, The Netherlands., Versteeg S; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, The Netherlands., van de Worp W; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, The Netherlands., Kanters DHAJ; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, The Netherlands., Reedquist KA; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, The Netherlands., Koenderman L; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, The Netherlands., Hack CE; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, The Netherlands., Eijkelkamp N; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, The Netherlands; n.eijkelkamp@umcutrecht.nl.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Mar 16; Vol. 118 (11).
DOI:	10.1073/pnas.2009647118
Abstrakt:	New therapeutic approaches to resolve persistent pain are highly needed. We tested the hypothesis that manipulation of cytokine receptors on sensory neurons by clustering regulatory cytokine receptor pairs with a fusion protein of interleukin (IL)-4 and IL-10 (IL4-10 FP) would redirect signaling pathways to optimally boost pain-resolution pathways. We demonstrate that a population of mouse sensory neurons express both receptors for the regulatory cytokines IL-4 and IL-10. This population increases during persistent inflammatory pain. Triggering these receptors with IL4-10 FP has unheralded biological effects, because it resolves inflammatory pain in both male and female mice. Knockdown of both IL4 and IL10 receptors in sensory neurons in vivo ablated the IL4-10 FP-mediated inhibition of inflammatory pain. Knockdown of either one of the receptors prevented the analgesic gain-of-function of IL4-10 FP. In vitro, IL4-10 FP inhibited inflammatory mediator-induced neuronal sensitization more effectively than the combination of cytokines, confirming its superior activity. The IL4-10 FP, contrary to the combination of IL-4 and IL-10, promoted clustering of IL-4 and IL-10 receptors in sensory neurons, leading to unique signaling, that is exemplified by activation of shifts in the cellular kinome and transcriptome. Interrogation of the potentially involved signal pathways led us to identify JAK1 as a key downstream signaling element that mediates the superior analgesic effects of IL4-10 FP. Thus, IL4-10 FP constitutes an immune-biologic that clusters regulatory cytokine receptors in sensory neurons to transduce unique signaling pathways required for full resolution of persistent inflammatory pain. Competing Interests: Competing interest statement: J.P., J.P.-C., C.S.-L., C.E.H., and N.E. have financial interest in Synerkine Pharma BV. Data have been used for patent filings. (Copyright © 2021 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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