气候变化领域集成服务门户(CCPortal): Cytokine receptor clustering in sensory neurons with an engineered cytokine fusion protein triggers unique pain resolution pathways

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DOI	10.1073/pnas.2009647118
	Cytokine receptor clustering in sensory neurons with an engineered cytokine fusion protein triggers unique pain resolution pathways
	Prado J.; Westerink R.H.S.; Popov-Celeketic J.; Steen-Louws C.; Pandit A.; Versteeg S.; Wouter van de Worp; Kanters D.H.A.J.; Reedquist K.A.; Koenderman L.; C. Erik Hack; Eijkelkamp N.
发表日期	2021
ISSN	00278424
卷号	118 期号:11
英文摘要	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 mediatorinduced 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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Antiinflammatory cytokines; Fusion protein; Inflammatory pain; Receptor clustering
语种	英语
scopus关键词	cytokine receptor; fusion protein; interleukin 10; interleukin 10 receptor; interleukin 4; interleukin 4 receptor; Janus kinase 1; protein c fos; transcriptome; animal experiment; Article; chronic pain; controlled study; female; gene expression; hyperalgesia; immune response; immune system; in vivo study; inflammatory pain; male; mouse; neuropathic pain; nonhuman; priority journal; protein expression; sensory nerve; sensory nerve cell; signal transduction; spinal cord injury
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180267
作者单位	Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, 3584 EA, Netherlands; Neurotoxicology Research Group, Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, 3584 CM, Netherlands; Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, 3584 EA, Netherlands
推荐引用方式 GB/T 7714	Prado J.,Westerink R.H.S.,Popov-Celeketic J.,et al. Cytokine receptor clustering in sensory neurons with an engineered cytokine fusion protein triggers unique pain resolution pathways[J],2021,118(11).
APA	Prado J..,Westerink R.H.S..,Popov-Celeketic J..,Steen-Louws C..,Pandit A..,...&Eijkelkamp N..(2021).Cytokine receptor clustering in sensory neurons with an engineered cytokine fusion protein triggers unique pain resolution pathways.Proceedings of the National Academy of Sciences of the United States of America,118(11).
MLA	Prado J.,et al."Cytokine receptor clustering in sensory neurons with an engineered cytokine fusion protein triggers unique pain resolution pathways".Proceedings of the National Academy of Sciences of the United States of America 118.11(2021).