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Activation of Sphingosine-1-Phosphate Receptor 1 in the Spinal Cord Produces Mechanohypersensitivity Through the Activation of Inflammasome and IL-1β Pathway

Published:February 22, 2019DOI:https://doi.org/10.1016/j.jpain.2019.02.007

      Highlights

      • Sphingosine-1-phosphate (S1P) receptor 1 subtype (S1PR1) mechanisms in the spinal cord producing mechanohypersensitivity are unknown.
      • S1PR1 activation causes mechanohypersensitivity via NLRP3 neuroinflammation.
      • The inhibition of S1PR1-mediated mechanohypersensitivity is dependent on IL-10.
      • Astrocytes are a cellular substrate for S1PR1 activity.

      Abstract

      Sphingosine-1-phosphate (S1P) receptor 1 subtype (S1PR1) activation by its ligand S1P in the dorsal horn of the spinal cord causes mechanohypersensitivity. The cellular and molecular pathways remain poorly understood. We report that the activation of S1PR1 with an intrathecal injection of the highly selective S1PR1 agonist SEW2871 led to the development of mechanoallodynia by activating the nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome (increased expression of NLRP3, cleaved caspase 1 and mature IL-1β) in the dorsal horn of the spinal cord. The functional S1PR1 antagonist FTY720 blocked NLRP3 activation and IL-1β production. Moreover, inhibiting IL-10 signaling with an intrathecal injection of an anti–IL-10 antibody attenuated the beneficial effects exerted by FTY720. This finding suggests that disrupting S1PR1 signaling engages beneficial IL-10–dependent pathways. Notably, we found that mice with astrocyte-specific deletions of S1pr1 did not develop mechanoallodynia after intrathecal injection of SEW2871 and exhibited decreased levels of cleaved caspase 1, identifying astrocytes as a key cellular locus for S1PR1 activity. Our findings provide novel mechanistic insights on how S1PR1 activation in the spinal cord contributes to the development of nociception while identifying the cellular substrate for these activities.

      Perspective

      This study is the first to link the activation of NLRP3 and IL-1β signaling in the spinal cord and S1PR1 signaling in astrocytes to the development of S1PR1-evoked mechanoallodynia. These findings provide critical basic science insights to support the development of therapies targeted toward S1PR1.

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      References

        • Abram SE
        • Yi J
        • Fuchs A
        • Hogan QH
        Permeability of injured and intact peripheral nerves and dorsal root ganglia.
        Anesthesiology. 2006; 105: 146-153
        • Bachstetter AD
        • Rowe RK
        • Kaneko M
        • Goulding D
        • Lifshitz J
        • Van Eldik LJ
        The p38alpha MAPK regulates microglial responsiveness to diffuse traumatic brain injury.
        J Neurosci. 2013; 33: 6143-6153
        • Ben Haim L
        • Ceyzeriat K
        • Carrillo-de Sauvage MA
        • Aubry F
        • Auregan G
        • Guillermier M
        • Ruiz M
        • Petit F
        • Houitte D
        • Faivre E
        • Vandesquille M
        • Aron-Badin R
        • Dhenain M
        • Deglon N
        • Hantraye P
        • Brouillet E
        • Bonvento G
        • Escartin C
        The JAK/STAT3 pathway is a common inducer of astrocyte reactivity in Alzheimer's and Huntington's diseases.
        J Neurosci. 2015; 35: 2817-2829
        • Billich A
        • Bornancin F
        • Mechtcheriakova D
        • Natt F
        • Huesken D
        • Baumruker T
        Basal and induced sphingosine kinase 1 activity in A549 carcinoma cells: Function in cell survival and IL-1beta and TNF-alpha induced production of inflammatory mediators.
        Cell Signal. 2005; 17: 1203-1217
        • Bryan L
        • Kordula T
        • Spiegel S
        • Milstien S
        Regulation and functions of sphingosine kinases in the brain.
        Biochim Biophys Acta. 2008; 1781: 459-466
        • Chi XX
        • Nicol GD
        The sphingosine 1-phosphate receptor, S1PR(1), plays a prominent but not exclusive role in enhancing the excitability of sensory neurons.
        J Neurophysiol. 2010; 104: 2741-2748
        • Choi JW
        • Gardell SE
        • Herr DR
        • Rivera R
        • Lee CW
        • Noguchi K
        • Teo ST
        • Yung YC
        • Lu M
        • Kennedy G
        • Chun J
        FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation.
        Proc Natl Acad Sci U S A. 2011; 108: 751-756
        • Coll RC
        • Robertson AA
        • Chae JJ
        • Higgins SC
        • Munoz-Planillo R
        • Inserra MC
        • Vetter I
        • Dungan LS
        • Monks BG
        • Stutz A
        • Croker DE
        • Butler MS
        • Haneklaus M
        • Sutton CE
        • Nunez G
        • Latz E
        • Kastner DL
        • Mills KH
        • Masters SL
        • Schroder K
        • Cooper MA
        • O'Neill LA
        A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases.
        Nat Med. 2015; 21: 248-255
        • Cordero MD
        • Alcocer-Gomez E
        • Culic O
        • Carrion AM
        • de Miguel M
        • Diaz-Parrado E
        • Perez-Villegas EM
        • Bullon P
        • Battino M
        • Sanchez-Alcazar JA
        NLRP3 inflammasome is activated in fibromyalgia: The effect of coenzyme Q10.
        Antioxid Redox Signal. 2013; 20: 1169-1180
        • Coste O
        • Brenneis C
        • Linke B
        • Pierre S
        • Maeurer C
        • Becker W
        • Schmidt H
        • Gao W
        • Geisslinger G
        • Scholich K
        Sphingosine 1-phosphate modulates spinal nociceptive processing.
        J Biol Chem. 2008; 283: 32442-32451
        • Coste O
        • Pierre S
        • Marian C
        • Brenneis C
        • Angioni C
        • Schmidt H
        • Popp L
        • Geisslinger G
        • Scholich K
        Antinociceptive activity of the S1P-receptor agonist FTY720.
        J Cell Mol Med. 2008; 12: 995-1004
        • Dixon WJ
        Efficient analysis of experimental observations.
        Annu Rev Pharmacol Toxicol. 1980; 20: 441-462
        • Dolunay A
        • Senol SP
        • Temiz-Resitoglu M
        • Guden DS
        • Sari AN
        • Sahan-Firat S
        • Tunctan B
        Inhibition of NLRP3 inflammasome prevents LPS-induced inflammatory hyperalgesia in mice: Contribution of NF-kappaB, caspase-1/11, ASC, NOX, and NOS isoforms.
        Inflammation. 2017; 40: 366-386
        • Doyle T
        • Bryant L
        • Chen Z
        • Cuzzocrea S
        • Salvemini D
        Morphine-induced antinociceptive tolerance and hyperalgesia is mediated through sphingosine 1-phosphate receptor 1-dependent p38 and neuroinflammatory mechanisms.
        J Pain. 2013; 14 (S42-S42)
        • Freeman L
        • Guo H
        • David CN
        • Brickey WJ
        • Jha S
        • Ting JP
        NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes.
        J Exp Med. 2017; 214: 1351-1370
        • Grace PM
        • Strand KA
        • Galer EL
        • Urban DJ
        • Wang X
        • Baratta MV
        • Fabisiak TJ
        • Anderson ND
        • Cheng K
        • Greene LI
        • Berkelhammer D
        • Zhang Y
        • Ellis AL
        • Yin HH
        • Campeau S
        • Rice KC
        • Roth BL
        • Maier SF
        • Watkins LR
        Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation.
        Proc Natl Acad Sci U S A. 2016; 113: E3441-E3450
        • Grenald SA
        • Doyle TM
        • Zhang H
        • Slosky LM
        • Chen Z
        • Largent-Milnes TM
        • Spiegel S
        • Vanderah TW
        • Salvemini D
        Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation.
        Pain. 2017; 158: 1733-1742
        • Hylden JL
        • Wilcox GL
        Intrathecal morphine in mice: A new technique.
        Eur J Pharmacol. 1980; 67: 313-316
        • Janes K
        • Little JW
        • Li C
        • Bryant L
        • Chen C
        • Chen Z
        • Kamocki K
        • Doyle T
        • Snider A
        • Esposito E
        • Cuzzocrea S
        • Bieberich E
        • Obeid L
        • Petrache I
        • Nicol G
        • Neumann WL
        • Salvemini D
        The development and maintenance of paclitaxel-induced neuropathic pain require activation of the sphingosine 1-phosphate receptor subtype 1.
        J Biol Chem. 2014; 289: 21082-21097
        • Ji RR
        • Chamessian A
        • Zhang YQ
        Pain regulation by non-neuronal cells and inflammation.
        Science. 2016; 354: 572-577
        • Johnston IN
        • Milligan ED
        • Wieseler-Frank J
        • Frank MG
        • Zapata V
        • Campisi J
        • Langer S
        • Martin D
        • Green P
        • Fleshner M
        • Leinwand L
        • Maier SF
        • Watkins LR
        A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine.
        J Neurosci. 2004; 24: 7353-7365
        • Kosmidou C
        • Efstathiou NE
        • Hoang MV
        • Notomi S
        • Konstantinou EK
        • Hirano M
        • Takahashi K
        • Maidana DE
        • Tsoka P
        • Young L
        • Gragoudas ES
        • Olsen TW
        • Morizane Y
        • Miller JW
        • Vavvas DG
        Issues with the specificity of immunological reagents for NLRP3: Implications for age-related macular degeneration.
        Sci Rep. 2018; 8: 461
        • Kummer JA
        • Broekhuizen R
        • Everett H
        • Agostini L
        • Kuijk L
        • Martinon F
        • van Bruggen R
        • Tschopp J
        Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response.
        J Histochem Cytochem. 2007; 55: 443-452
        • Lee H
        • Deng J
        • Kujawski M
        • Yang C
        • Liu Y
        • Herrmann A
        • Kortylewski M
        • Horne D
        • Somlo G
        • Forman S
        • Jove R
        • Yu H
        STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors.
        Nat Med. 2010; 16: 1421-1428
        • Liu W
        • Tang Y
        • Feng J
        Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system.
        Life Sci. 2011; 89: 141-146
        • Lobo-Silva D
        • Carriche GM
        • Castro AG
        • Roque S
        • Saraiva M
        Balancing the immune response in the brain: IL-10 and its regulation.
        J Neuroinflamm. 2016; 13: 297
        • Marchand F
        • Perretti M
        • McMahon SB
        Role of the immune system in chronic pain.
        Nat Rev Neurosci. 2005; 6: 521-532
        • Muscoli C
        • Doyle T
        • Dagostino C
        • Bryant L
        • Chen Z
        • Watkins LR
        • Ryerse J
        • Bieberich E
        • Neumman W
        • Salvemini D
        Counter-regulation of opioid analgesia by glial-derived bioactive sphingolipids.
        J Neurosci. 2010; 30: 15400-15408
        • Nayak D
        • Huo Y
        • Kwang WX
        • Pushparaj PN
        • Kumar SD
        • Ling EA
        • Dheen ST
        Sphingosine kinase 1 regulates the expression of proinflammatory cytokines and nitric oxide in activated microglia.
        Neuroscience. 2010; 166: 132-144
        • Norden DM
        • Fenn AM
        • Dugan A
        • Godbout JP
        TGFbeta produced by IL-10 redirected astrocytes attenuates microglial activation.
        Glia. 2014; 62: 881-895
        • Norden DM
        • Trojanowski PJ
        • Walker FR
        • Godbout JP
        Insensitivity of astrocytes to interleukin 10 signaling following peripheral immune challenge results in prolonged microglial activation in the aged brain.
        Neurobiol Aging. 2016; 44: 22-41
        • O'Sullivan C
        • Dev KK
        The structure and function of the S1P1 receptor.
        Trends Pharmacol Sci. 2013; 34: 401-412
        • Qasimi P
        • Ming-Lum A
        • Ghanipour A
        • Ong CJ
        • Cox ME
        • Ihle J
        • Cacalano N
        • Yoshimura A
        • Mui AL
        Divergent mechanisms utilized by SOCS3 to mediate interleukin-10 inhibition of tumor necrosis factor alpha and nitric oxide production by macrophages.
        J Biol Chem. 2006; 281: 6316-6324
        • Ren K
        • Torres R
        Role of interleukin-1beta during pain and inflammation.
        Brain Res Rev. 2009; 60: 57-64
        • Rothhammer V
        • Kenison JE
        • Tjon E
        • Takenaka MC
        • de Lima KA
        • Borucki DM
        • Chao CC
        • Wilz A
        • Blain M
        • Healy L
        • Antel J
        • Quintana FJ
        Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation.
        Proc Natl Acad Sci U S A. 2017; 114: 2012-2017
        • Salvemini D
        • Doyle T
        • Kress M
        • Nicol G
        Therapeutic targeting of the ceramide-to-sphingosine 1-phosphate pathway in pain.
        Trends Pharmacol Sci. 2013; 34: 110-118
        • Sanna MG
        • Wang SK
        • Gonzalez-Cabrera PJ
        • Don A
        • Marsolais D
        • Matheu MP
        • Wei SH
        • Parker I
        • Jo E
        • Cheng WC
        • Cahalan MD
        • Wong CH
        • Rosen H
        Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo.
        Nat Chem Biol. 2006; 2: 434-441
        • Schnoder L
        • Hao W
        • Qin Y
        • Liu S
        • Tomic I
        • Liu X
        • Fassbender K
        • Liu Y
        Deficiency of Neuronal p38alpha MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1.
        J Biol Chem. 2016; 291: 2067-2079
        • Sennepin AD
        • Charpentier S
        • Normand T
        • Sarre C
        • Legrand A
        • Mollet LM
        Multiple reprobing of Western blots after inactivation of peroxidase activity by its substrate, hydrogen peroxide.
        Anal Biochem. 2009; 393: 129-131
        • Sim-Selley LJ
        • Wilkerson JL
        • Burston JJ
        • Hauser KF
        • McLane V
        • Welch SP
        • Lichtman AH
        • Selley DE
        Differential tolerance to FTY720-induced antinociception in acute thermal and nerve injury mouse pain models: Role of S1P receptor adaptation.
        J Pharmacol Exp Ther. 2018; 366: 509-518
        • Song N
        • Liu ZS
        • Xue W
        • Bai ZF
        • Wang QY
        • Dai J
        • Liu X
        • Huang YJ
        • Cai H
        • Zhan XY
        • Han QY
        • Wang H
        • Chen Y
        • Li HY
        • Li AL
        • Zhang XM
        • Zhou T
        • Li T
        NLRP3 phosphorylation is an essential priming event for inflammasome activation.
        Mol Cell. 2017; 68 (e186): 185-197
        • Spiegel S
        • Milstien S
        The outs and the ins of sphingosine-1-phosphate in immunity.
        Nat Rev Immunol. 2011; 11: 403-415
        • Stockstill K
        • Doyle TM
        • Yan X
        • Chen Z
        • Janes K
        • Little JW
        • Braden K
        • Lauro F
        • Giancotti LA
        • Harada CM
        • Yadav R
        • Xiao WH
        • Lionberger JM
        • Neumann WL
        • Bennett GJ
        • Weng HR
        • Spiegel S
        • Salvemini D
        Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain.
        J Exp Med. 2018; 215: 1301-1313
        • Sung CS
        • Wen ZH
        • Chang WK
        • Ho ST
        • Tsai SK
        • Chang YC
        • Wong CS
        Intrathecal interleukin-1beta administration induces thermal hyperalgesia by activating inducible nitric oxide synthase expression in the rat spinal cord.
        Brain Res. 2004; 1015: 145-153
        • Tsuchiya K
        • Hara H
        The inflammasome and its regulation.
        Crit Rev Immunol. 2014; 34: 41-80
        • Wahlman C
        • Doyle TM
        • Little JW
        • Luongo L
        • Janes K
        • Chen Z
        • Esposito E
        • Tosh DK
        • Cuzzocrea S
        • Jacobson KA
        • Salvemini D
        Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels through astrocyte-dependent mechanisms.
        Pain. 2018; 159: 1025-1034
        • Watkins LR
        • Milligan ED
        • Maier SF
        Glial activation: A driving force for pathological pain.
        Trends Neurosci. 2001; 24: 450-455
        • Weichand B
        • Popp R
        • Dziumbla S
        • Mora J
        • Strack E
        • Elwakeel E
        • Frank AC
        • Scholich K
        • Pierre S
        • Syed SN
        • Olesch C
        • Ringleb J
        • Oren B
        • Doring C
        • Savai R
        • Jung M
        • von Knethen A
        • Levkau B
        • Fleming I
        • Weigert A
        • Brune B
        S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1beta.
        J Exp Med. 2017; 214: 2695-2713
        • Wu C
        • Leong SY
        • Moore CS
        • Cui QL
        • Gris P
        • Bernier LP
        • Johnson TA
        • Seguela P
        • Kennedy TE
        • Bar-Or A
        • Antel JP
        Dual effects of daily FTY720 on human astrocytes in vitro: Relevance for neuroinflammation.
        J Neuroinflamm. 2013; 10: 41
        • Wu YP
        • Mizugishi K
        • Bektas M
        • Sandhoff R
        • Proia RL
        Sphingosine kinase 1/S1P receptor signaling axis controls glial proliferation in mice with Sandhoff disease.
        Human Mol Genet. 2008; 17: 2257-2264
        • Zhang RX
        • Li A
        • Liu B
        • Wang L
        • Ren K
        • Zhang H
        • Berman BM
        • Lao L
        IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats.
        Pain. 2008; 135: 232-239
        • Zhang Y
        • Chen K
        • Sloan SA
        • Bennett ML
        • Scholze AR
        • O'Keeffe S
        • Phatnani HP
        • Guarnieri P
        • Caneda C
        • Ruderisch N
        • Deng S
        • Liddelow SA
        • Zhang C
        • Daneman R
        • Maniatis T
        • Barres BA
        • Wu JQ
        An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex.
        J Neurosci. 2014; 34: 11929-11947
        • Zhang YH
        • Vasko MR
        • Nicol GD
        Intracellular sphingosine 1-phosphate mediates the increased excitability produced by nerve growth factor in rat sensory neurons.
        J Physiol. 2006; 575: 101-113