Cytokine receptor clustering in sensory neurons with an engineered cytokine fusion protein triggers unique pain resolution pathways.
antiinflammatory cytokines
fusion protein
inflammatory pain
receptor clustering
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
16 03 2021
16 03 2021
Historique:
entrez:
10
4
2021
pubmed:
11
4
2021
medline:
15
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33836560
pii: 2009647118
doi: 10.1073/pnas.2009647118
pmc: PMC7980471
pii:
doi:
Substances chimiques
Cytokines
0
Receptors, Cytokine
0
Recombinant Fusion Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2021 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
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.
Références
Purinergic Signal. 2005 Jun;1(2):95-100
pubmed: 18404495
Nat Rev Immunol. 2014 Apr;14(4):217-31
pubmed: 24577438
Brain Res. 2000 Dec 1;885(1):79-86
pubmed: 11121532
Mol Pain. 2006 Feb 17;2:6
pubmed: 16503976
Sci STKE. 2004 Apr 28;2004(231):re7
pubmed: 15126678
Elife. 2017 May 12;6:
pubmed: 28498099
Neuropsychopharmacology. 2018 Dec;43(13):2597-2605
pubmed: 30054585
Eur J Pharmacol. 2013 Sep 15;716(1-3):106-19
pubmed: 23500198
Pharm Res. 2010 May;27(5):841-54
pubmed: 20224990
J Neurosci. 2015 Jan 14;35(2):457-66
pubmed: 25589741
Nucleic Acids Res. 2015 Jan;43(Database issue):D662-9
pubmed: 25352552
Mol Cancer Ther. 2002 Mar;1(5):347-55
pubmed: 12489851
Pain. 2007 Nov;132(1-2):195-205
pubmed: 17890011
Nat Med. 2010 Nov;16(11):1267-76
pubmed: 20948535
Neuromodulation. 2012 Nov-Dec;15(6):520-6; discussion 526
pubmed: 22672183
BMC Musculoskelet Disord. 2008 Jul 15;9:102
pubmed: 18627605
Osteoarthritis Cartilage. 2018 Aug;26(8):1127-1135
pubmed: 29775732
Eur J Pain. 2006 May;10(4):287-333
pubmed: 16095934
Mol Biol Cell. 2010 Aug 1;21(15):2797-807
pubmed: 20554759
Pain. 2018 Jul;159(7):1325-1345
pubmed: 29561359
Brain Behav Immun. 2007 Jul;21(5):686-98
pubmed: 17174526
Anal Biochem. 1976 May 7;72:248-54
pubmed: 942051
Brain Res Bull. 2010 Jan 15;81(1):157-63
pubmed: 19818386
Arthritis Rheum. 2006 Aug;54(8):2656-64
pubmed: 16871547
JAKSTAT. 2013 Oct 1;2(4):e27638
pubmed: 24470980
Eur J Immunol. 2010 Feb;40(2):443-8
pubmed: 19941312
Nat Commun. 2013;4:1682
pubmed: 23575686
J Neurosci Methods. 1994 Jul;53(1):55-63
pubmed: 7990513
Exp Neurol. 2015 Sep;271:198-204
pubmed: 26079835
Neuroscientist. 2014 Jun;20(3):291-304
pubmed: 24047609
J Neurosci. 2010 Feb 10;30(6):2138-49
pubmed: 20147541
Adv Immunol. 2014;121:1-39
pubmed: 24388212
Exp Neurol. 2012 Apr;234(2):255-61
pubmed: 22273537
Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12706-11
pubmed: 15314237
Exp Neurol. 2012 Apr;234(2):354-61
pubmed: 22116040
Front Immunol. 2019 Dec 23;10:3009
pubmed: 31921220
Neurosci Lett. 1996 Oct 25;218(1):17-20
pubmed: 8939470
Methods. 2008 Jul;45(3):227-32
pubmed: 18620061
Glia. 2011 Apr;59(4):554-68
pubmed: 21319222
PLoS One. 2013 Jul 01;8(7):e69405
pubmed: 23840913
Eur Spine J. 2002 Oct;11(5):467-75
pubmed: 12384756
Proc Natl Acad Sci U S A. 2015 Dec 8;112(49):E6808-17
pubmed: 26598697
J Neurosci. 2016 Jul 13;36(28):7353-63
pubmed: 27413147
Pain. 1988 Jan;32(1):77-88
pubmed: 3340425
J Neurosci. 2016 Oct 26;36(43):11074-11083
pubmed: 27798187
Mol Pain. 2009 Mar 27;5:16
pubmed: 19327151
Science. 2008 Aug 1;321(5889):702-5
pubmed: 18669863
Exp Neurol. 2013 Sep;247:466-75
pubmed: 23357618
Pain. 2020 Oct;161(10):2344-2352
pubmed: 32427749
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Stem Cells Transl Med. 2015 Jan;4(1):66-73
pubmed: 25391644
Rheumatology (Oxford). 2018 Mar 1;57(3):429-440
pubmed: 28968842
Brain Res. 1993 Apr 2;607(1-2):195-204
pubmed: 8481796
J Neurosci Res. 1998 Jul 15;53(2):203-13
pubmed: 9671977
Pharm Res. 2019 Dec 26;37(2):17
pubmed: 31879800
J Biol Chem. 2001 Nov 23;276(47):43901-8
pubmed: 11572871
Cell. 2017 Sep 21;171(1):217-228.e13
pubmed: 28890086
Annu Rev Biophys Biomol Struct. 1993;22:329-51
pubmed: 7688610
Annu Rev Immunol. 2009;27:29-60
pubmed: 18817510
Toxicol Sci. 2015 Oct;147(2):607-17
pubmed: 26187449
Front Mol Neurosci. 2019 Sep 11;12:216
pubmed: 31572125
Brain Behav Immun. 2018 Feb;68:158-168
pubmed: 29056557
Nat Neurosci. 2015 Jan;18(1):145-53
pubmed: 25420068
Neuroscience. 1998 Sep;86(1):257-63
pubmed: 9692759
PLoS Biol. 2018 Feb 14;16(2):e2003452
pubmed: 29444090
J Pain. 2014 May;15(5):496-506
pubmed: 24793056
Neurochem Res. 2015 Apr;40(4):733-9
pubmed: 25617163
Nat Neurosci. 2016 Jan;19(1):94-101
pubmed: 26642091
Science. 2016 Nov 4;354(6312):572-577
pubmed: 27811267
Adv Drug Deliv Rev. 2003 Aug 28;55(8):1081-112
pubmed: 12935946
J Immunol. 2010 Oct 15;185(8):4804-11
pubmed: 20861354
Cell. 1990 Apr 20;61(2):203-12
pubmed: 2158859
J Vis Exp. 2018 Apr 11;(134):
pubmed: 29708532
Brain Res. 1995 Dec 24;705(1-2):91-6
pubmed: 8821738
J Neuroimmunol. 2008 Mar;195(1-2):157-63
pubmed: 18325600
Brain Behav Immun. 2018 Mar;69:91-112
pubmed: 29113923
Sci Rep. 2016 Jul 26;6:30459
pubmed: 27456198