Cytokine receptor clustering in sensory neurons with an engineered cytokine fusion protein triggers unique pain resolution pathways.
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
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发表时间：
2021-03-16
影响因子：
11.1
通讯作者：
Eijkelkamp N
中科院分区：
文献类型：
--
作者：
Prado J;Westerink RHS;Popov-Celeketic J;Steen-Louws C;Pandit A;Versteeg S;van de Worp W;Kanters DHAJ;Reedquist KA;Koenderman L;Hack CE;Eijkelkamp N
免疫系统和神经系统之间的相互作用调节慢性疼痛。细胞因子是众所周知的免疫调节分子，其具有超出免疫系统调节的活性，包括调节疼痛途径。我们鉴定了调节性细胞因子白细胞介素（IL）-4和IL-10融合到融合蛋白IL 4 -10 FP中通过聚集感觉神经元中两种细胞因子的各自受体链提供了意想不到的抑制疼痛的性质。IL 4 -10 FP促进解决慢性炎性疼痛的独特信号通路和基因表达谱。因此，IL 4 -10 FP是一种免疫生物制剂，其通过细胞因子受体的聚集激活感觉神经元中的疼痛消退途径来有效抑制疼痛。这种独特的作用将IL 4 -10 FP与单独的调节细胞因子的组合疗法区分开来。迫切需要新的治疗方法来解决持续性疼痛。我们测试了这样一种假设，即通过将调节性细胞因子受体对与白细胞介素（IL）-4和IL-10（IL-4 -10 FP）的融合蛋白聚集在一起来操纵感觉神经元上的细胞因子受体，将重定向信号传导通路，以最佳地促进疼痛缓解通路。我们证明，一个人口的小鼠感觉神经元表达两种受体的调节细胞因子IL-4和IL-10。这一群体在持续性炎症性疼痛期间增加。用IL 4 -10 FP触发这些受体具有未知的生物学效应，因为它解决了雄性和雌性小鼠的炎性疼痛。在体内感觉神经元中IL 4和IL 10受体的敲低消除了IL 4 -10 FP介导的对炎性疼痛的抑制。敲低任一受体可阻止IL 4 -10 FP的镇痛功能获得。在体外，IL 4 -10 FP比细胞因子的组合更有效地抑制炎症介质诱导的神经元敏化，证实了其上级活性。与IL-4和IL-10的组合相反，IL-4 -10 FP促进感觉神经元中IL-4和IL-10受体的聚集，导致独特的信号传导，其通过细胞激酶组和转录组中的转变的激活来例示。对可能涉及的信号通路的询问使我们鉴定JAK 1为介导IL 4 -10 FP的上级镇痛作用的关键下游信号传导元件。因此，IL 4 -10 FP构成了一种免疫生物制剂，其聚集感觉神经元中的调节性细胞因子受体，以阻断完全解决持续性炎性疼痛所需的独特信号传导途径。
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. 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.
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