Tackling Pain Associated with Rheumatoid Arthritis: Proton-Sensing Receptors

  • Wei-Hsin SunEmail author
  • Shih-Ping Dai
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1099)


Rheumatoid arthritis (RA), characterized by chronic inflammation of synovial joints, is often associated with ongoing pain and increased pain sensitivity. Chronic pain that comes with RA turns independent, essentially becoming its own disease. It could partly explain that a significant number (50%) of RA patients fail to respond to current RA therapies that focus mainly on suppression of joint inflammation. The acute phase of pain seems to associate with joint inflammation in early RA. In established RA, the chronic phase of pain could be linked to inflammatory components of neuron-immune interactions and noninflammatory components. Accumulating evidence suggests that the initial inflammation and autoimmunity in RA (preclinical RA) begin outside of the joint and may originate at mucosal sites and alterations in the composition of microbiota located at mucosal sites could be essential for mucosal inflammation, triggering joint inflammation. Fibroblast-like synoviocytes in the inflamed joint respond to cytokines to release acidic components, lowering pH in synovial fluid. Extracellular proton binds to proton-sensing ion channels, and G-protein-coupled receptors in joint nociceptive fibers may contribute to sensory transduction and release of neurotransmitters, leading to pain and hyperalgesia. Activation of peripheral sensory neurons or nociceptors further modulates inflammation, resulting in neuroinflammation or neurogenic inflammation. Peripheral and central nerves work with non-neuronal cells (such as immune cells, glial cells) in concert to contribute to the chronic phase of RA-associated pain. This review will discuss actions of proton-sensing receptors on neurons or non-neuronal cells that modulate RA pathology and associated chronic pain, and it will be beneficial for the development of future therapeutic treatments.


Rheumatoid arthritis Chronic pain Proton-sensing receptors Neuron-immune interaction Gut microbiota 


  1. 1.
    Abdollahi-Roodsaz S, Joosten LA, Koenders MI, Devesa I, Roelofs MF, Radstake TR, Heuvelmans-Jacobs M, Akira S, Nicklin MJ, Ribeiro-Dias F, van den Berg WB (2008) Stimulation of TLR2 and TLR4 differentially skews the balance of T-cells in a mouse model of arthritis. J Clin Invest 118:205–216CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Al-Mossawi MH, Chen L, Fang H, Ridley A, de Wit J, Yager N, Hammitzsch A, Pulyakhina I, Fairfax BP, Simone D, Yi Y, Bandyopadhyay S, Doig K, Gundle R, Kendrick B, Powrie F, Knight JC, Bowness P (2017) Unique transcriptome signatures and GM-CSF expression in lymphocytes from patients with spondyloarthritis. Nat Commun 8(1):1510CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Atzeni F, Cazzola M, Benucci M, Di Franco M, Salaffi F, Sarzi-Puttini P (2011) Chronic widespread pain in the spectrum of rheumatological diseases. Best Pract Res Clin Rheumatol 25(2):165–171CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bas DB, Su J, Sandor K, Agalave NM, Lundberg J, Codeluppi S, Baharpoor A, Nandakumar KS, Holmdahl R, Svensson CI (2012) Collagen antibody-induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency. Arthritis Rheum 64(12):3886–3896CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    von Banchet GS, Richter J, Hückel M, Rose C, Bräuer R, Schaible HG (2007) Fibroblast-like synovial cells from normal and inflamed knee joints differently affect the expression of pain-related receptors in sensory neurones: a co-culture study. Arthritis Res Ther 9:R6CrossRefGoogle Scholar
  6. 6.
    Barton NJ, McQueen DS, Thomson D, Gauldie SD, Wilson AW, Salter DM, Chessell IP (2006) Attenuation of experimental arthritis in TRPV1R knockout mice. Exp Mol Pathol 81:166–170CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Bennett G, Al-Rashed S, Hoult JR, Brain SD (1998) Nerve growth factor induced hyperalgesia in the rat hind paw is dependent on circulating neutrophils. Pain 77:315–322CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Brack A, Rittner HL, Machelska H, Leder K, Mousa SA, Schäfer M, Stein C (2004) Control of inflammatory pain by chemokine-mediated recruitment of opioid-containing polymorphonuclear cells. Pain 112(3):229–238CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Borenstein D, Altman R, Bello A, Chatham W, Clauw DJ, Crofford LJ et al (2010) Report of the American College of Rheumatology Pain Management Task Force. Arthritis Care Res 62(5):590–599CrossRefGoogle Scholar
  10. 10.
    Borbély É, Botz B, Bölcskei K, Kenyér T, Kereskai L, Kiss T, Szolcsányi J, Pintér E, Csepregi JZ, Mócsai A, Helyes Z (2015) Capsaicin-sensitive sensory nerves exert complex regulatory functions in the serum-transfer mouse model of autoimmune arthritis. Brain Behav Immun 45:50–59CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Chen J, Wright K, Davis JM, Jeraldo P, Marietta EV, Murray J, Nelson H, Matteson EL, Taneja V (2016) An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med 8(1):43CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Chen WN, Lee CH, Lin SH, Wong CW, Sun WH, Wood JN, Chen CC (2014) Roles of ASIC3, TRPV1, and NaV1.8 in the transition from acute to chronic pain in a mouse model of fibromyalgia. Mol Pain 10:40CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Chen Y, Willcockson HH, Valtschanoff JG (2009) Influence of the vanilloid receptor TRPV1 on the activation of spinal cord glia in mouse models of pain. Exp Neurol 220(2):383–390CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Chiu IM, Heesters BA, Ghasemlou N, Von Hehn CA, Zhao F, Tran J, Wainger B, Strominger A, Muralidharan S, Horswill AR, Bubeck Wardenburg J, Hwang SW, Carroll MC, Woolf CJ (2013) Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501(7465):52–57CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Courvoisier N, Dougados M, Cantagrel A, Goupille P, Meyer O, Sibilia J, Daures JP, Combe B (2008) Prognostic factors of 10-year radiographic outcome in early rheumatoid arthritis: a prospective study. Arthritis Res Ther 10(5):1186CrossRefGoogle Scholar
  16. 16.
    Cortes A, Hadler J, Pointon JP, Robinson PC, Karaderi T, Leo P, Cremin K, Pryce K, Harris J, Lee S, Joo KB, Shim SC, Weisman M, Ward M, Zhou X, Garchon HJ, Chiocchia G, Nossent J, Lie BA, Førre Ø, Tuomilehto J, Laiho K, Jiang L, Liu Y, Wu X, Bradbury LA, Elewaut D, Burgos-Vargas R, Stebbings S, Appleton L, Farrah C, Lau J, Kenna TJ, Haroon N, Ferreira MA, Yang J, Mulero J, Fernandez-Sueiro JL, Gonzalez-Gay MA, Lopez-Larrea C, Deloukas P, Donnelly P, Australo-Anglo-American Spondyloarthritis Consortium (TASC); Groupe Française d'Etude Génétique des Spondylarthrites (GFEGS), Nord-Trøndelag Health Study (HUNT); Spondyloarthritis Research Consortium of Canada (SPARCC), Wellcome Trust Case Control Consortium 2 (WTCCC2), Bowness P, Gafney K, Gaston H, Gladman DD, Rahman P, Maksymowych WP, Xu H, Crusius JB, van der Horst-Bruinsma IE, Chou CT, Valle-Oñate R, Romero-Sánchez C, Hansen IM, Pimentel-Santos FM, Inman RD, Videm V, Martin J, Breban M, Reveille JD, Evans DM, Kim TH, Wordsworth BP, Brown MA (2013) Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet 45(7):730–738CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Christensen BN, Kochukov M, McNearney TA, Taglialatela G, Westlund KN (2005) Proton-sensing G protein-coupled receptor mobilizes calcium in human synovial cells. Am J Phys Cell Phys 289:C601–C608CrossRefGoogle Scholar
  18. 18.
    Cua DJ, Tato CM (2010) Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol 10(7):479–489CrossRefGoogle Scholar
  19. 19.
    Dai SP, Huang YH, Chang CJ, Huang YF, Hsieh WS, Tabata Y, Ishii S, Sun WH (2017) TDAG8 involved in initiating inflammatory hyperalgesia and establishing hyperalgesic priming in mice. Sci Rep 7:41415CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Demoruelle MK, Deane KD, Holers VM (2014) When and where does inflammation begin in rheumatoid arthritis? Curr Opin Rheumatol 26(1):64–71CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Diogenes A, Ferraz CC, Akopian AN, Henry MA, Hargreaves KM (2011) LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons. J Dent Res 90(6):759–764CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Doly S, Fischer J, Salio C, Conrath M (2004) The vanilloid receptor-1 is expressed in rat spinal dorsal horn astrocytes. Neurosci Lett 357(2):123–126CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ebbinghaus M, Segond Von Banchet G, Massier J, Gajda M, Bräuer R, Kress M, Schaible HG (2015) Interleukin-6-dependent influence of nociceptive sensory neurons on antigen-induced arthritis. Arthritis Res Ther 17:334CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Ebbinghaus M, Natura G, Segond von Banchet G, Hensellek S, Böttcher M, Hoffmann B, Salah FS, Gajda M, Kamradt T, Schaible HG (2017) Interleukin-17A is involved in mechanical hyperalgesia but not in the severity of murine antigen-induced arthritis. Sci Rep 7(1):10334CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Engler A, Aeschlimann A, Simmen BR, Michel BA, Gay RE, Gay S, Sprott H (2007) Expression of transient receptor potential vanilloid 1 (TRPV1) in synovial fibroblasts from patients with osteoarthritis and rheumatoid arthritis. Biochem Biophys Res Commun 359:884–888CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ek M, Kurosawa M, Lundeberg T, Ericsson A (1998) Activation of vagal afferents after intravenous injection of interleukin-1beta: role of endogenous prostaglandins. J Neurosci 18:9471–9479CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Edwards RR, Wasan AD, Bingham CO 3rd, Bathon J, Haythorn-thwaite JA, Smith MT et al (2009) Enhanced reactivity to pain in patients with rheumatoid arthritis. Arthritis Res Ther 11:R61CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Farr M, Garvey K, Bold AM, Kendall MJ, Bacon PA (1985) Significance of the hydrogen ion centration in synovial fluid in rheumatoid arthritis. Clin Exp Rheumatol 3:99–104PubMedPubMedCentralGoogle Scholar
  29. 29.
    Fernandes ES, Russell FA, Spina D, McDougall JJ, Graepel R, Gentry C, Staniland AA, Mountford DM, Keeble JE, Malcangio M, Bevan S, Brain SD (2011) A distinct role for transient receptor potential ankyrin 1, in addition to transient receptor potential vanilloid 1, in tumor necrosis factor α-induced inflammatory hyperalgesia and Freund’s complete adjuvant-induced monarthritis. Arthritis Rheum 63:819–829CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423:356–361CrossRefGoogle Scholar
  31. 31.
    Gaublomme JT, Yosef N, Lee Y, Gertner RS, Yang LV, Wu C, Pandolfi PP, Mak T, Satija R, Shalek AK, Kuchroo VK, Park H, Regev A (2015) Single-cell genomics unveils critical regulators of Th17 cell pathogenicity. Cell 163(6):1400–1412CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Goesling J, Clauw DJ, Hassett AL (2013) Pain and depression: an integrative review of neurobiological and psychological factors. Curr Psychiatry Rep 15(12):421CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Guillemin F, Briançon S, Pourel J (1992) Functional disability in rheumatoid arthritis: two different models in early and established disease. J Rheumatol 19(3):366–369PubMedPubMedCentralGoogle Scholar
  34. 34.
    Hamilton JA, Tak PP (2009) Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum 60(5):1210–1221CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Hang LH, Yang JP, Yin W, Wang LN, Guo F, Ji FH, Shao DH, Xu QN, Wang XY, Zuo JL (2012) Activation of spinal TDAG8 and its downstream PKA signaling pathway contribute to bone cancer pain in rats. Eur J Neurosci 36:2107–2117CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Hikiji H, Endo D, Horie K, Harayama T, Akahoshi N, Igarashi H, Kihara Y, Yanagida K, Takeda J, Koji T, Shimizu T, Ishii S (2014) TDAG8 activation inhibits osteoclastic bone resorption. FASEB J 28:871–879CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Heiberg T, Finset A, Uhlig T, Kvien TK (2005) Seven year changes in health status and priorities for improvement of health in patients with rheumatoid arthritis. Ann Rheum Dis 64(2):191–195CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Hess A, Axmann R, Rech J, Finzel S, Heindl C, Kreitz S et al (2011) Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. PNAS 108:3731–3736CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Hsieh WS, Kung CC, Huang SL, Lin SC, Sun WH (2017) TDAG8, TRPV1, and ASIC3 involved in establishing hyperalgesic priming in experimental rheumatoid arthritis. Sci Rep 7:8870CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Huang YH, Su YS, Chang CJ, Sun WH (2016) Heteromerization of OGR1 and G2A enhance proton signaling. J Recept Signal Transduct 6:1–12 [Epub ahead of print]Google Scholar
  41. 41.
    Hu W, Chen FH, Yuan FL, Zhang TY, Wu FR, Rong C, Jiang S, Tang J, Zhang CC, Lin MY (2012) Blockade of acid-sensing ion channels protects articular chondrocytes from acid-induced apoptotic injury. Inflamm Res 61:327–335CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Ikeuchi M, Kolker SJ, Burnes LA, Walder RY, Sluka KA (2008) Role of ASIC3 in the primary and secondary hyperalgesia produced by joint inflammation in mice. Pain 137:662–669CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Ikeuchi M, Kolker SJ, Sluka KA (2009) Acid-sensing ion channel 3 expression in mouse knee joint afferents and effects of carrageenan-induced arthritis. J Pain 10:336–342CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Ishii S, Kihara Y, Shimizu T (2005) Identification of T cell death-associated gene 8 (TDAG8) as a novel acid sensing G-protein coupled receptor. J Biol Chem 280:9083–9087CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Izumi M, Ikeuchi M, Ji Q, Tani T (2012) Local ASIC3 modulates pain and disease progression in a rat model of osteoarthritis. J Biomed Sci 19:77CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Ji RR, Chamessian A, Zhang YQ (2016) Pain regulation by non-neuronal cells and inflammation. Science 354:572–577CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Jin Y, Sato K, Tobo A, Mogi C, Tobo M, Murata N, Ishii S, Im DS, Okajima F (2014) Inhibition of interleukin-1β production by extracellular acidification through the TDAG8/cAMP pathway in mouse microglia. J Neurochem 129:683–695CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Julius D (2013) TRP channels and pain. Annu Rev Cell Dev Biol 29:355–384CrossRefGoogle Scholar
  49. 49.
    Kennedy A, Fearon U, Veale DJ, Godson C (2011) Macrophages in synovial inflammation. Front Immunol 2:52CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Kim SR, Kim SU, Oh U, Jin BK (2006) Transient receptor potential vanilloid subtype 1 mediates microglial cell death in vivo and in vitro via Ca2+-mediated mitochondrial damage and cytochrome c release. J Immunol 177(7):4322–4329CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    ten Klooster PM, Veehof MM, Taal E, van Riel PL, van de Laar MA (2007) Changes in priorities for improvement in patients with rheumatoid arthritis during 1 year of anti-tumour necrosis factor treatment. Ann Rheum Dis 66(11):1485–1490CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Kochukov MY, McNearney TA, Fu Y, Westlund KN (2006) Thermosensitive TRP ion channels mediate cytosolic calcium response in human synoviocytes. Am J Phys Cell Phys 291:C424–C432CrossRefGoogle Scholar
  53. 53.
    Kolker SJ, Walder RY, Usachev Y, Hillman J, Boyle DL, Firestein GS, Sluka KA (2010) Acid-sensing ion channel 3 expressed in type B synoviocytes and chondrocytes modulates hyaluronan expression and release. Ann Rheum Dis 69:903–909CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Kong X, Tang X, Du W, Tong J, Yan Y, Zheng F, Fang M, Gong F, Tan Z (2013) Extracellular acidosis modulates the endocytosis and maturation of macrophages. Cell Immunol 281:44–50CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S, Schuurman PR, Mehta AD, Levine YA, Faltys M, Zitnik R, Tracey KJ, Tak PP (2016) Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A 113(29):8284–8289CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Lee YC, Cui J, Lu B, Frits ML, Iannaccone CK, Shadick NA, Weinblatt ME, Solomon DH (2011a) Pain persists in DAS28 rheumatoid arthritis remission but not in ACR/EULAR remission: a longitudinal observational study. Arthritis Res Ther 13(3):R83CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Lee YC, Nassikas NJ, Clauw DJ (2011b) The role of the central nervous system in the generation and maintenance of chronic pain in rheumatoid arthritis, osteoarthritis and fibromyalgia. Arthritis Res Ther 13(2):211CrossRefGoogle Scholar
  58. 58.
    Levine JD, Gooding J, Donatoni P, Borden L, Goetzl EJ (1985) The role of the polymorphonuclear leukocyte in hyperalgesia. J Neurosci 5:3025–3029CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Levine JD, Lam D, Taiwo YO, Donatoni P, Goetzl EJ (1986) Hyperalgesic properties of 15-lipoxygenase products of arachidonic acid. Proc Natl Acad Sci U S A 83:5331–5334CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Lin SH, Sun WH, Chen CC (2014) Genetic exploration of the role of acid-sensing ion channels. Neuropharmocology 94:99–118CrossRefGoogle Scholar
  61. 61.
    Lin SH, Steinhoff M, Ikoma A, Chang YC, Cheng YR, Chandra Kopparaju R, Ishii S, Sun WH, Chen CC (2017) Involvement of TRPV1 and TDAG8 in pruriception associated with noxious acidosis. J Invest Dermatol 137:170–178CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Liu X, Zeng B, Zhang J, Li W, Mou F, Wang H, Zou Q, Zhong B, Wu L, Wei H, Fang Y (2016) Role of the gut microbiome in modulating arthritis progression in mice. Sci Rep 6:30594CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Luczynski P, Tramullas M, Viola M, Shanahan F, Clarke G, O'Mahony S, Dinan TG, Cryan JF (2017) Microbiota regulates visceral pain in the mouse. Elife 6. pii: e25887Google Scholar
  64. 64.
    McWilliams DF, Zhang W, Mansell JS, Kiely PD, Young A, Walsh DA (2012) Predictors of change in bodily pain in early rheumatoid arthritis: an inception cohort study. Arthritis Care Res 64(10):1505–1513CrossRefGoogle Scholar
  65. 65.
    Milanova V, Ivanovska N, Dimitrova P (2014) TLR2 elicits IL-17-mediated RANKL expression, IL-17, and OPG production in neutrophils from arthritic mice. Mediat Inflamm 2014:643–406CrossRefGoogle Scholar
  66. 66.
    Mirakaj V, Dalli J, Granja T, Rosenberger P, Serhan CN (2014) Vagus nerve controls resolution and pro-resolving mediators of inflammation. J Exp Med 211(6):1037–1048CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Mogi C, Tobo M, Tomura H, Murata N, He XD, Sato K, Kimura T, Ishizuka T, Sasaki T, Sato T, Kihara Y, Ishii S, Harada A, Okajima F (2009) Involvement of proton-sensing TDAG8 in extracellular acidification-induced inhibition of proinflammatory cytokine production in peritoneal macrophages. J Immunol 182:3243–3251CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Navegantes KC, de Souza GR, Pereira P, Czaikoski P, Azevedo C, Monteiro MC (2017) Immune modulation of some autoimmune diseases: the critical role of macrophages and neutrophils in the innate and adaptive immunity. J Transl Med 15:36CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Nieto FR, Clark AK, Grist J, Hathway GJ, Chapman V, Malcangio M (2016) Neuron-immune mechanisms contribute to pain in early stages of arthritis. J Neuroinflammation 13:96CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    OʼMahony SM, Dinan TG, Cryan JF (2017) The gut microbiota as a key regulator of visceral pain. Pain 158:S19–S28CrossRefGoogle Scholar
  71. 71.
    Onozawa Y, Fujita Y, Kuwabara H, Nagasaki M, Komai T, Oda T (2012) Activation of T cell death-associated gene 8 regulates the cytokine production of T cells and macrophages in vitro. Eur J Pharmacol 683:325–331CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Onozawa Y, Komai T, Oda T (2011) Activation of T cell death-associated gene 8 attenuates inflammation by negatively regulating the function of inflammatory cells. Eur J Pharmacol 654(3):315–319CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Pianta A, Arvikar S, Strle K, Drouin EE, Wang Q, Costello CE, Steere AC (2017) Evidence of the immune relevance of Prevotella copri, a gut microbe, in patients with rheumatoid arthritis. Arthritis Rheum 69:964–975CrossRefGoogle Scholar
  74. 74.
    Parak WJ, Dannohl S, George M, Schuler MK, Schaumburger J, Gaub HE, Muller O, Aicher WK (2000) Metabolic activation stimulates acid production in synovial fibroblasts. J Rheumatol 27:2312–2322PubMedPubMedCentralGoogle Scholar
  75. 75.
    Raggi F, Pelassa S, Pierobon D, Penco F, Gattorno M, Novelli F, Eva A, Varesio L, Giovarelli M, Bosco MC (2017) Regulation of human macrophage M1-M2 polarization balance by hypoxia and the triggering receptor expressed on myeloid Cells-1. Front Immunol 8:1097CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Reeh PW, Steen KH (1996) Tissue acidosis in nociception and pain. Prog Brain Res 113:143–151CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Richter F, Natura G, Ebbinghaus M, von Banchet GS, Hensellek S, König C, Bräuer R, Schaible HG (2012) Interleukin-17 sensitizes joint nociceptors to mechanical stimuli and contributes to arthritic pain through neuronal interleukin-17 receptors in rodents. Arthritis Rheum 64(12):4125–4134CrossRefGoogle Scholar
  78. 78.
    Rogier R, Evans-Marin H, Manasson J, van der Kraan PM, Walgreen B, Helsen MM, van den Bersselaar LA, van de Loo FA, van Lent PL, Abramson SB, van den Berg WB, Koenders MI, Scher JU, Abdollahi-Roodsaz S (2017) Alteration of the intestinal microbiome characterizes preclinical inflammatory arthritis in mice and its modulation attenuates established arthritis. Sci Rep 7(1):15613CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Rong C, Chen FH, Jiang S, Hu W, Wu FR, Chen TY, Yuan FL (2012) Inhibition of acid-sensing ion channels by amiloride protects rat articular chondrocytes from acid-induced apoptosis via a mitochondrial-mediated pathway. Cell Biol Int 36(7):635–641. CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Schaible HG, Grubb BD (1993) Afferent and spinal mechanisms of joint pain. Pain 55:5–54CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Scher JU, Ubeda C, Artacho A, Attur M, Isaac S, Reddy SM, Marmon S, Neimann A, Brusca S, Patel T, Manasson J, Pamer EG, Littman DR, Abramson SB (2015) Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheum 67(1):128–139CrossRefGoogle Scholar
  82. 82.
    Shen S, Lim G, You Z, Ding W, Huang P, Ran C, Doheny J, Caravan P, Tate S, Hu K, Kim H, McCabe M, Huang B, Xie Z, Kwon D, Chen L, Mao J (2017) Gut microbiota is critical for the induction of chemotherapy-induced pain. Nat Neurosci 20(9):1213–1216CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Shu HF, Wang BR, Wang SR, Yao W, Huang HP, Zhou Z, Wang X, Fan J, Wang T, Ju G (2007) IL-1beta inhibits IK and increases [Ca2+]i in the carotid body glomus cells and increases carotid sinus nerve firings in the rat. Eur J Neurosci 25(12):3638–3647CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Sluka KA, Rasmussen LA, Edgar MM, O'Donnell JM, Walder RY, Kolker SJ, Boyle DL, Firestein GS (2013) Acid-sensing ion channel 3 deficiency increases inflammation but decreases pain behavior in murine arthritis. Arthritis Rheum 65:1194–1202CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Soehnlein O, Steffens S, Hidalgo A, Weber C (2017) Neutrophils as protagonists and targets in chronic inflammation. Nat Rev Immunol 17(4):248–261CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Steinberg BE, Sundman E, Terrando N, Eriksson LI, Olofsson PS (2016) Neural control of inflammation: implications for perioperative and critical care. Anesthesiology 124(5):1174–1189CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Stangenberg L, Burzyn D, Binstadt BA, Weissleder R, Mahmood U, Benoist C, Mathis D (2014) Denervation protects limbs from inflammatory arthritis via an impact on the microvasculature. Proc Natl Acad Sci U S A 111(31):11419–11424CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Studenic P, Radner H, Smolen JS, Aletaha D (2012) Discrepancies between patients and physicians in their perceptions of rheumatoid arthritis disease activity. Arthritis Rheum 64(9):2814–2823CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Sun WH, Chen CC (2016) Roles of proton-sensing receptors in the transition from acute to chronic pain. J Dent Res 95:135–142CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Su YS, Sun WH, Chen CC (2014) Molecular mechanism of inflammatory pain. World J Anesthesiol 3:71–81CrossRefGoogle Scholar
  91. 91.
    Szabó A, Helyes Z, Sándor K, Bite A, Pintér E, Németh J, Bánvölgyi A, Bölcskei K, Elekes K, Szolcsányi J (2005) Role of transient receptor potential vanilloid 1 receptors in adjuvant-induced chronic arthritis: in vivo study using gene-deficient mice. J Pharmacol Exp Ther 314:111–119CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Tak PP, Smeets TJ, Daha MR, Kluin PM, Meijers KA, Brand R, Meinders AE, Breedveld FC (1997) Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum 40(2):217–225CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Tsuneyoshi Y, Tanaka M, Nagai T, Sunahara N, Matsuda T, Sonoda T, Ijiri K, Komiya S, Matsuyama T (2012) Functional folate receptor beta-expressing macrophages in osteoarthritis synovium and their M1/M2 expression profiles. Scand J Rheumatol 41(2):132–140CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Vandooren B, Noordenbos T, Ambarus C, Krausz S, Cantaert T, Yeremenko N, Boumans M, Lutter R, Tak PP, Baeten D (2009) Absence of a classically activated macrophage cytokine signature in peripheral spondylarthritis, including psoriatic arthritis. Arthritis Rheum 60(4):966–975CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Wang JQ, Kon J, Mogi C, Tobo M, Damirin A, Sato K, Komachi M, Malchinkhuu E, Murata N, Kimura T, Kuwabara A, Wakamatsu K, Koizumi H, Uede T, Tsujimoto G, Kurose H, Sato T, Harada A, Misawa N, Tomura H, Okajima F (2004) TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor. J Biol Chem 279:45626–45633CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Wolfe F, Michaud K (2007) Assessment of pain in rheumatoid arthritis: minimal clinically significant difference, predictors, and the effect of anti-tumor necrosis factor therapy. J Rheumatol 34(8):1674–1683PubMedPubMedCentralGoogle Scholar
  97. 97.
    Wigerblad G, Bas DB, Fernades-Cerqueira C, Krishnamurthy A, Nandakumar KS, Rogoz K, Kato J, Sandor K, Su J, Jimenez-Andrade JM, Finn A, Bersellini Farinotti A, Amara K, Lundberg K, Holmdahl R, Jakobsson PJ, Malmström V, Catrina AI, Klareskog L, Svensson CI (2016) Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism. Ann Rheum Dis 75(4):730–738CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Wilkins RJ, Hall AC (1995) Control of matrix synthesis in isolated bovine chondrocytes by extracellular and intracellular pH. J Cell Physiol 164:474–481CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Williams EK, Chang RB, Strochlic DE, Umans BD, Lowell BB, Liberles SD (2016) Sensory neurons that detect stretch and nutrients in the digestive system. Cell 166(1):209–221CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Wipke BT, Allen PM (2001) Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis. J Immunol 167(3):1601–1608CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Wright HL, Moots RJ, Bucknall RC, Edwards SW (2010) Neutrophil function in inflammation and inflammatory diseases. Rheumatology (Oxford) 49(9):1618–1631CrossRefGoogle Scholar
  102. 102.
    Wu HJ, Ivanov II, Darce J, Hattori K, Shima T, Umesaki Y, Littman DR, Benoist C, Mathis D (2010) Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32(6):815–827CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Wu MH, Urban JP, Cui ZF, Cui Z, Xu X (2007) Effect of extracellular pH on matrix synthesis by chondrocytes in 3D agarose gel. Biotechnol Prog 23:430–434CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Yuan FL, Chen FH, Lu WG, Li X, Li JP, Li CW, Xu RS, Wu FR, Hu W, Zhang TY (2010) Inhibition of acid-sensing ion channels in articular chondrocytes by amiloride attenuates articular cartilage destruction in rats with adjuvant arthritis. Inflamm Res 59:939–947CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Zapata P, Larraín C, Reyes P, Fernández R (2011) Immunosensory signalling by carotid body chemoreceptors. Respir Physiol Neurobiol 178(3):370–374CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Zhang X, Zhang D, Jia H, Feng Q, Wang D, Liang D, Wu X, Li J, Tang L, Li Y, Lan Z, Chen B, Li Y, Zhong H, Xie H, Jie Z, Chen W, Tang S, Xu X, Wang X, Cai X, Liu S, Xia Y, Li J, Qiao X, Al-Aama JY, Chen H, Wang L, Wu QJ, Zhang F, Zheng W, Li Y, Zhang M, Luo G, Xue W, Xiao L, Li J, Chen W, Xu X, Yin Y, Yang H, Wang J, Kristiansen K, Liu L, Li T, Huang Q, Li Y, Wang J (2015) The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med 21(8):895–905CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of Life SciencesNational Central UniversityTaoyuan CityTaiwan

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