TY - JOUR
T1 - Cytokine receptor clustering in sensory neurons with an engineered cytokine fusion protein triggers unique pain resolution pathways
AU - Prado, Judith
AU - Westerink, Remco H S
AU - Popov-Celeketic, Jelena
AU - Steen-Louws, Cristine
AU - Pandit, Aridaman
AU - Versteeg, Sabine
AU - van de Worp, Wouter
AU - Kanters, Deon H A J
AU - Reedquist, Kris A
AU - Koenderman, Leo
AU - Hack, C Erik
AU - Eijkelkamp, Niels
N1 - Funding Information:
(University Medical Center Utrecht) and Savithri Rangarajan (PamGene International) for PAMgene support; Fiona Wijnolts for calcium imaging support; and the Utrecht Sequencing Facility for providing sequencing service and data. The Utrecht Sequencing Facility is subsidized by the University Medical Center Utrecht, Hubrecht Institute, Utrecht University, and The Netherlands X-omics Initiative (Dutch Research Council Project 184.034.019). This work has received funding from the Life Sciences Seed grant of the University Utrecht. This work is part of the research programme “Open Technology Programme” with Project 16907, which is (partly) financed by the Dutch Research Council.
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/3/16
Y1 - 2021/3/16
N2 - 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.
AB - 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.
KW - Antiinflammatory cytokines
KW - Fusion protein
KW - Inflammatory pain
KW - Receptor clustering
UR - http://www.scopus.com/inward/record.url?scp=85102355103&partnerID=8YFLogxK
U2 - 10.1073/pnas.2009647118
DO - 10.1073/pnas.2009647118
M3 - Article
C2 - 33836560
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 11
M1 - e2009647118
ER -