TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization

Abstract

Cutaneous neurogenic inflammation (CNI) is inflammation that is induced (or enhanced) in the skin by the release of neuropeptides from sensory nerve endings. Clinical manifestations are mainly sensory and vascular disorders such as pruritus and erythema. Transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively) are non-selective cation channels known to specifically participate in pain and CNI. Both TRPV1 and TRPA1 are co-expressed in a large subset of sensory nerves, where they integrate numerous noxious stimuli. It is now clear that the expression of both channels also extends far beyond the sensory nerves in the skin, occuring also in keratinocytes, mast cells, dendritic cells, and endothelial cells. In these non-neuronal cells, TRPV1 and TRPA1 also act as nociceptive sensors and potentiate the inflammatory process. This review discusses the role of TRPV1 and TRPA1 in the modulation of inflammatory genes that leads to or maintains CNI in sensory neurons and non-neuronal skin cells. In addition, this review provides a summary of current research on the intracellular sensitization pathways of both TRP channels by other endogenous inflammatory mediators that promote the self-maintenance of CNI.

Key words： sensory nerve; neurogenic skin inflammation; inflammatory gene regulation; pruritus

References

1 AhnS, Siddiqi MH, AceitunoVC (2016) Ginsenoside Rg5:Rk1 attenuates TNF-α/IFN-γ-induced production of thymus- and activation-regulated chemokine (TARC/CCL17) and LPS-induced NO production via downregulation of NF-κB/p38 MAPK/STAT1 signaling in human keratinocytes and macrophages.In Vitro Cell Dev Biol Anim52:287–295.

2 AkaishiS, OgawaR, HyakusokuH (2008) Keloid and hypertrophic scar: neurogenic inflammation hypotheses.Med Hypotheses71:32–38.

3 AkiyamaT, IvanovM, NagamineM (2016) Involvement of TRPV4 in serotonin-evoked scratching.J Invest Dermatol136:154–160.

4 AkopianAN, Ruparel NB, JeskeNA , HargreavesKM (2007) Transient receptor potential TRPA1 channel desensitization in sensory neurons is agonist dependent and regulated by TRPV1-directed internalization.J Physiol583:175–193.

5 AlpizarYA, BoonenB, GeesM (2013) Allyl isothiocyanate sensitizes TRPV1 to heat stimulation.Pflüg Arch—Eur J Physiol466:507–515.

6 AmadesiS, NieJ, VergnolleN (2004) Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia.J Neurosci Off J Soc Neurosci24:4300–4312.

7 AmadesiS, Cottrell GS, DivinoL (2006) Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cε- and A-dependent mechanisms in rats and mice.J Physiol575:555–571.

8 AnandU, OttoWR, FacerP (2008) TRPA1 receptor localisation in the human peripheral nervous system and functional studies in cultured human and rat sensory neurons.Neurosci Lett438:221–227.

9 AnderssonDA, GentryC, MossS, Bevan S (2008) Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress.J Neurosci Off J Soc Neurosci28:2485–2494.

10 AndreevYA, Vassilevski AA, KozlovSA (2012) Molecules to selectively target receptors for treatment of pain and neurogenic inflammation.Recent Pat Inflamm Allergy Drug Discov6:35–45

11 AsfahaS, CenacN, HouleS (2007) Protease-activated receptor-4: a novel mechanism of inflammatory pain modulation.Br J Pharmacol150:176–185.

12 AtoyanR, Shander D, BotchkarevaNV (2009)Non-neuronal expression of transient receptor potential type A1 (TRPA1) in human skin.J Invest Dermatol129:2312–2315.

13 AubdoolAA, BrainSD (2011) Neurovascular aspects of skin neurogenic inflammation.J Investig Dermatol Symp Proc Soc Investig Dermatol Inc Eur Soc Dermatol Res15:33–39.

14 BandellM, StoryGM, HwangSW (2004) Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin.Neuron41:849–857

15 BasuS, Srivastava P (2005) Immunological role of neuronal receptor vanilloid receptor 1 expressed on dendritic cells.Proc Natl Acad Sci U S A102:5120–5125.

16 BautistaDM, JordtS-E, NikaiT (2006) TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents.Cell124:1269–1282.

17 BautistaDM, Pellegrino M, TsunozakiM (2013) TRPA1: A gatekeeper for inflammation.Annu Rev Physiol75:181–200.

18 BhaveG, ZhuW, WangH (2002) cAMP-dependent protein kinase regulates desensitization of the capsaicin receptor (VR1) by direct phosphorylation.Neuron35:721–731

19 BhaveG, HuH-J, GlaunerKS (2003) Protein kinase C phosphorylation sensitizes but does not activate the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1).Proc Natl Acad Sci U S A100:12480–12485.

20 BilleterAT, Galbraith N, WalkerS (2015) TRPA1 mediates the effects of hypothermia on the monocyte inflammatory response.Surgery158:646–654.

21 BinshtokAM, WangH, ZimmermannK (2008) Nociceptors are interleukin-1β sensors.J Neurosci Off J Soc Neurosci28:14062–14073.

22 BíróT, Kovács L (2009) An “ice-cold” TR(i)P to skin biology: the role of TRPA1 in human epidermal keratinocytes.J Invest Dermatol129:2096–2099.

23 Bı́róT, Maurer M, ModarresS (1998) Characterization of functional vanilloid receptors expressed by mast cells. Blood91:1332–1340

24 BoillatA, Alijevic O, KellenbergerS (2014) Calcium entry via TRPV1 but not ASICs induces neuropeptide release from sensory neurons.Mol Cell Neurosci61C:13–22.

25 BriotA, Deraison C, LacroixM (2009) Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome.J Exp Med206:1135–1147.

26 BunkerCB, CerioR, BullHA (1991) The effect of capsaicin application on mast cells in normal human skin.Agents Actions33:195–196

27 BurgessGM, Mullaney I, McNeillM (1989) Second messengers involved in the mechanism of action of bradykinin in sensory neurons in culture.J Neurosci9:3314–3325

28 CalixtoJB, Kassuya CAL, AndréE , FerreiraJ (2005) Contribution of natural products to the discovery of the transient receptor potential (TRP) channels family and their functions.Pharmacol Ther106:179–208.

29 CaterinaMJ, Schumacher MA, TominagaM (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway.Nature389:816–824.

30 CesareP, Moriondo A, VellaniV , McNaughtonPA (1999) Ion channels gated by heat.Proc Natl Acad Sci U S A96:7658–7663

31 ChaoLK, HuaK-F, HsuH-Y (2008) Cinnamaldehyde inhibits pro-inflammatory cytokines secretion from monocytes/macrophages through suppression of intracellular signaling.Food Chem Toxicol Int J Publ Br Ind Biol Res Assoc46:220–231.

32 ChenJ, ZhangX-F, KortME (2008) Molecular determinants of species-specific activation or blockade of TRPA1 channels.J Neurosci28:5063–5071.

33 ChenY, YangC, WangZJ (2011) Proteinase-activated receptor 2 sensitizes transient receptor potential vanilloid 1, transient receptor potential vanilloid 4, and transient receptor potential ankyrin 1 in paclitaxel-induced neuropathic pain.Neuroscience193:440–451.

34 ChenD, WangZ, ZhangZ (2013) Capsaicin up-regulates protease-activated receptor-4 mRNA and protein in primary cultured dorsal root ganglion neurons.Cell Mol Neurobiol33:337–346.

35 ChingL-C, KouYR, ShyueS-K (2011) Molecular mechanisms of activation of endothelial nitric oxide synthase mediated by transient receptor potential vanilloid type 1.Cardiovasc Res91:492–501.

36 ChoiS-I,YooS, LimJY, Hwang SW (2014) Are sensory TRP channels biological alarms for lipid peroxidation?Int J Mol Sci15:16430–16457.

37 ChuangHH, Prescott ED, KongH (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition.Nature411:957–962.

38 ChungG, ImST, KimYH (2014) Activation of transient receptor potential ankyrin 1 by eugenol.Neuroscience261:153–160.

39 CocksTM, Moffatt JD (2000) Protease-activated receptors: sentries for inflammation?Trends Pharmacol Sci21:103–108.

40 CostaA, Eberlin S, PolettiniAJ (2014) Neuromodulatory and anti-inflammatory ingredient for sensitive skin: in vitro assessment.Inflamm Allergy Drug Targets13:191–198

41 DaiY, Moriyama T, HigashiT (2004) Proteinase-activated receptor 2-mediated potentiation of transient receptor potential vanilloid subfamily 1 activity reveals a mechanism for proteinaseinduced inflammatory pain.J Neurosci Off J Soc Neurosci24:4293–4299.

42 DaiY, WangS, TominagaM (2007) Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain.J Clin Invest117:1979–1987.

43 DiogenesA, Akopian AN, HargreavesKM (2007) NGF up-regulates TRPA1: implications for orofacial pain.J Dent Res86:550–555

44 DochertyRJ, YeatsJC, BevanS, Boddeke HW (1996) Inhibition of calcineurin inhibits the desensitization of capsaicin-evoked currents in cultured dorsal root ganglion neurones from adult rats.Pflüg Arch Eur J Physiol431:828–837

45 DoernerJF, Gisselmann G, HattH , WetzelCH (2007) Transient receptor potential channel A1 is directly gated by calcium ions.J Biol Chem282:13180–13189.

46 EarleyS, Gonzales AL, CrnichR (2009) Endothelium-dependent cerebral artery dilation mediated by TRPA1 and Ca2+-Activated K+ channels.Circ Res104:987–994.

47 EngelMA, Leffler A, NiedermirtlF (2011) TRPA1 and substance P mediate colitis in mice.Gastroenterology141:1346–1358.

48 FischerMJM, Balasuriya D, JeggleP (2014) Direct evidence for functional TRPV1/TRPA1 heteromers.Pflugers Arch.

49 FrydasS, Varvara G, MurmuraG (2013) Impact of capsaicin on mast cell inflammation.Int J Immunopathol Pharmacol26:597–600

50 FuQ, ChengJ, GaoY (2014) Protease-activated receptor 4: a critical participator in inflammatory response.Inflammation.

51 GouinO, Lebonvallet N, L’HerondelleK (2015) Self-maintenance of neurogenic inflammation contributes to a vicious cycle in skin.Exp Dermatol.

52 HerbertMK, HolzerP (2002) Neurogenic inflammation. I. Basic mechanisms, physiology and pharmacology.Anästhesiol Intensivmed Notfallmedizin Schmerzther AINS37:314–325.

53 HimiN, Hamaguchi A, HashimotoK (2012) Calcium influx through the TRPV1 channel of endothelial cells (ECs) correlates with a stronger adhesion between monocytes and ECs.Adv Med Sci57:224–229.

54 HinmanA, ChuangH-H, BautistaDM, Julius D (2006) TRP channel activation by reversible covalent modification.Proc Natl Acad Sci U S A103:19564–19568.

55 HondaK, Shinoda M, FurukawaA (2014) TRPA1 contributes to capsaicin-induced facial cold hyperalgesia in rats.Eur J Oral Sci.

56 HoogerwerfWA, ZouL, ShenoyM (2001) The proteinaseactivated receptor 2 is involved in nociception.J Neurosci Off J Soc Neurosci21:9036–9042

57 HorváthG, Kemény Á, BarthóL (2015) Effects of some natural carotenoids on TRPA1- and TRPV1-induced neurogenic inflammatory processes in vivo in the mouse skin.J Mol Neurosci MN.

58 HsuH-Y, WenM-H (2002) Lipopolysaccharide-mediated reactive oxygen species and signal transduction in the regulation of interleukin-1 gene expression.J Biol Chem277:22131–22139.

59 HuangL-YM, NeherE (1996) Ca2+-dependent exocytosis in the somata of dorsal root ganglion neurons.Neuron17:135–145.

60 HuangSM, Bisogno T, TrevisaniM (2002) An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors.Proc Natl Acad Sci U S A99:8400–8405.

61 HuangJ, StohlLL, ZhouX (2011) Calcitonin gene-related peptide inhibits chemokine production by human dermal microvascular endothelial cells.Brain Behav Immun25:787–799.

62 HwangSW, ChoH, KwakJ (2000) Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicinlike substances.Proc Natl Acad Sci U S A97:6155–6160

63 ImamachiN, ParkGH, LeeH (2009) TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms.Proc Natl Acad Sci U S A106:11330–11335.

64 InoueK, Koizumi S, FuziwaraS (2002) Functional vanilloid receptors in cultured normal human epidermal keratinocytes.Biochem Biophys Res Commun291:124–129.

65 JainA, Brönneke S, KolbeL (2011) TRP-channel-specific cutaneous eicosanoid release patterns.Pain152:2765–2772. doi:10.1016/j.pain.2011.08.025

66 JancsóN, Jancsó-Gábor A, SzolcsányiJ (1967) Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin.Br J Pharmacol Chemother31:138–151

67 JansR, SartorM, JadotM, Poumay Y (2004) Calcium entry into keratinocytes induces exocytosis of lysosomes.Arch Dermatol Res296:30–41.

68 JeskeNA, Patwardhan AM, GamperN (2006) Cannabinoid WIN 55,212-2 regulates TRPV1 phosphorylation in sensory neurons.J Biol Chem281:32879–32890.

69 JiaX, ZhangH, CaoX (2014) Activation of TRPV1 mediates thymic stromal lymphopoietin release via the Ca2+/NFAT pathway in airway epithelial cells.FEBS Lett588:3047–3054.

70 JianT, YangN, YangY (2016) TRPV1 and PLC participate in histamine H4 receptor-induced itch. Neural Plast2016:1682972.

71 JordtS-E, Bautista DM, ChuangH-H (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1.Nature427:260–265.

72 JungJ, ShinJS, LeeS-Y (2004) Phosphorylation of vanilloid receptor 1 by Ca2+/calmodulin-dependent kinase II regulates its vanilloid binding.J Biol Chem279:7048–7054.

73 KarashimaY, PrenenJ, MeseguerV (2008) Modulation of the transient receptor potential channel TRPA1 by phosphatidylinositol 4,5-biphosphate manipulators. Pflüg Arch Eur J Physiol457:77–89.

74 KarkT, BagiZ, LizaneczE (2008) Tissue-specific regulation of microvascular diameter: opposite functional roles of neuronal and smooth muscle located vanilloid receptor-1.Mol Pharmacol73:1405–1412.

75 KimD, Cavanaugh EJ, SimkinD (2008) Inhibition of transient receptor potential A1 channel by phosphatidylinositol-4,5-bisphosphate.Am J Physiol Cell Physiol295:C92–99.

76 KimCG, KangM, LeeY-H (2015) Bathing effects of various seawaters on allergic (atopic) dermatitis-like skin lesions induced by 2,4-dinitrochlorobenzene in hairless mice.Evid-Based Complement Altern Med ECAM2015:179185.

77 KimS, BarryDM, LiuX-Y (2016) Facilitation of TRPV4 by TRPV1 is required for itch transmission in some sensory neuron populations.Sci Signal9:ra71.

78 KohWS, YoonSY, KwonBM (1998) Cinnamaldehyde inhibits lymphocyte proliferation and modulates T-cell differentiation.Int J Immunopharmacol20:643–660

79 KubanovAA, Katunina OR, ChikinVV (2015) Expression of neuropeptides, neurotrophins, and neurotransmitters in the skin of patients with atopic dermatitis and psoriasis.Bull Exp Biol Med159:318–322.

80 KürkçüoğluN , AlaybeyiF (1991) Substance P immunoreactivity in rosacea.J Am Acad Dermatol25:725–726

81 KwakIS, ChoiYH, JangYC, Lee YK (2014) Immunohistochemical analysis of neuropeptides (protein gene product 9.5, substance P and calcitonin gene-related peptide) in hypertrophic burn scar with pain and itching.Burns40:1661–1667.

82 LeeYM, KimYK, KimKH (2009) A novel role for the TRPV1 channel in UV-induced matrix metalloproteinase (MMP)-1 expression in HaCaTcells.J Cell Physiol219:766–775.

83 LeeYM, KangSM, LeeSR (2011) Inhibitory effects of TRPV1 blocker on UV-induced responses in the hairless mice.Arch Dermatol Res303:727–736.

84 LiaoB-C, HsiehC-W, LiuY-C (2008) Cinnamaldehyde inhibits the tumor necrosis factor-α-induced expression of cell adhesion molecules in endothelial cells by suppressing NF-κB activation: Effects upon IκB and Nrf2.Toxicol Appl Pharmacol229:161–171.

85 LiaoM, CaoE, JuliusD, Cheng Y (2013) Structure of the TRPV1 ion channel determined by electron cryo-microscopy.Nature504:107–112.

86 LinZ, ChenQ, LeeM (2012) Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.Am J Hum Genet90:558–564.

87 LiuB, Escalera J, BalakrishnaS (2013) TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis.FASEB J Off Publ Fed Am Soc Exp Biol27:3549–3563.

88 LuoD, ZhangY-W, PengW-J (2008) Transient receptor potential vanilloid 1-mediated expression and secretion of endothelial cell-derived calcitonin gene-related peptide.Regul Pept150:66–72.

89 MacphersonLJ, Geierstanger BH, ViswanathV (2005) The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin.Curr Biol CB15:929–934.

90 MacphersonLJ, DubinAE, EvansMJ (2007) Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines.Nature445:541–545.

91 MalinS, Molliver D, ChristiansonJA (2011) TRPV1 and TRPA1 function and modulation are target tissue dependent.J Neurosci Off J Soc Neurosci31:10516–10528.

92 McNamaraCR, Mandel-Brehm J, BautistaDM (2007) TRPA1 mediates formalin-induced pain.Proc Natl Acad Sci U S A104:13525–13530.

93 MeseguerV, Alpizar YA, LuisE (2014) TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins.Nat Commun5:3125.

94 MishraSK, HoonMA (2010) Ablation of TrpV1 neurons reveals their selective role in thermal pain sensation.Mol Cell Neurosci43:157–163.

95 MishraSK, TiselSM, OrestesP (2011) TRPV1-lineage neurons are required for thermal sensation.EMBO J30:582–593.

96 MizumuraK, Sugiura T, KatanosakaK (2009) Excitation and sensitization of nociceptors by bradykinin: what do we know?Exp Brain Res196:53–65.

97 MohapatraDP, NauC (2003) Desensitization of capsaicin-activated currents in the vanilloid receptor TRPV1 is decreased by the cyclic AMP-dependent protein kinase pathway.J Biol Chem278:50080–50090.

98 MohapatraDP, NauC (2005) Regulation of Ca2+-dependent desensitization in the vanilloid receptor TRPV1 by calcineurin and cAMP-dependent protein kinase.J Biol Chem280:13424–13432.

99 MoniagaCS, JeongSK, EgawaG (2013) Protease activity enhances production of thymic stromal lymphopoietin and basophil accumulation in flaky tail mice.Am J Pathol182:841–851.

100 NakahigashiK, Kabashima K, IkomaA (2011) Upregulation of aquaporin-3 is involved in keratinocyte proliferation and epidermal hyperplasia.J Invest Dermatol131:865–873.

101 NakanishiM, HataK, NagayamaT (2010) Acid activation of Trpv1 leads to an up-regulation of calcitonin gene-related peptide expression in dorsal root ganglion neurons via the CaMK-CREB cascade: a potential mechanism of inflammatory pain.Mol Biol Cell21:2568–2577.

102 NobbeS, Dziunycz P, MühleisenB (2012) IL-31 expression by inflammatory cells is preferentially elevated in atopic dermatitis.Acta Derm Venereol92:24–28.

103 NumazakiM, Tominaga T, ToyookaH , TominagaM (2002) Direct phosphorylation of capsaicin receptor VR1 by protein kinase Cepsilon and identification of two target serine residues.J Biol Chem277:13375–13378.

104 ObataK, Katsura H, MizushimaT (2005) TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury.J Clin Invest115:2393–2401.

105 OlssonM, Broberg A, JernåsM (2006) Increased expression of aquaporin 3 in atopic eczema.Allergy61:1132–1137.

106 OpréeA, KressM (2000) Involvement of the proinflammatory cytokines tumor necrosis factor-alpha, IL-1 beta, and IL-6 but not IL-8 in the development of heat hyperalgesia: effects on heatevoked calcitonin gene-related peptide release from rat skin.J Neurosci Off J Soc Neurosci20:6289–6293

107 OrmerodAD, WellerR, CopelandP (1998) Detection of nitric oxide and nitric oxide synthases in psoriasis.Arch Dermatol Res290:3–8

108 OstadhadiS, Haj-Mirzaian A, AzimiE (2015) Involvement of nitric oxide in serotonin-induced scratching in mice.Clin Exp Dermatol40:647–652.

109 PatilMJ, JeskeNA, AkopianAN (2010) Transient receptor potential V1 regulates activation and modulation of transient receptor potential A1 by Ca2+.Neuroscience171:1109–1119.

110 PatricioES, CostaR, FigueiredoCP (2015) Mechanisms underlying the scratching behavior induced by the activation of proteinase-activated receptor-4 in mice.J Invest Dermatol135:2484–2491.

111 PatwardhanAM, JeskeNA, PriceTJ (2006) The cannabinoidWIN 55,212-2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin.Proc Natl Acad Sci U S A103:11393–11398.

112 PaulsenCE, Armache J-P, GaoY (2015) Structure of the TRPA1 ion channel suggests regulatory mechanisms.Nature520:511–517.

113 PertovaaraA, Koivisto A (2011) TRPA1 ion channel in the spinal dorsal horn as a therapeutic target in central pain hypersensitivity and cutaneous neurogenic inflammation.Eur J Pharmacol666:1–4.

114 PetrusM, PeierAM, BandellM (2007) A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition.Mol Pain3:40.

115 PrescottED, JuliusD (2003) A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity.Science300:1284–1288.

116 QianX, Francis M, SolodushkoV (2013) Recruitment of dynamic endothelial Ca2+ signals by the TRPA1 channel activator AITC in rat cerebral arteries.Microcirc N Y N 199420:138–148.

117 RajasekharP, PooleDP, LiedtkeW (2015) P2Y1 receptor activation of the TRPV4 ion channel enhances purinergic signaling in satellite glial cells.J Biol Chem290:29051–29062.

118 Riol-BlancoL, Ordovas-Montanes J, PerroM (2014) Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation.Nature510:157–161.

119 RomanoB, Borrelli F, FasolinoI (2013) The cannabinoid TRPA1 agonist cannabichromene inhibits nitric oxide production in macrophages and ameliorates murine colitis.Br J Pharmacol169:213–229.

120 RoostermanD, GoergeT, SchneiderSW (2006) Neuronal control of skin function: the skin as a neuroimmunoendocrine organ.Physiol Rev86:1309–1379.

121 RussellFA, Veldhoen VE, TchitchkanD , McDougallJJ (2010) Proteinase-activated receptor-4 (PAR4) activation leads to sensitization of rat joint primary afferents via a bradykinin B2 receptor-dependent mechanism.J Neurophysiol103:155–163.

122 SalasMM, Hargreaves KM, AkopianAN (2009) TRPA1-mediated responses in trigeminal sensory neurons: interaction between TRPA1 and TRPV1.Eur J Neurosci29:1568–1578.

123 SalemSAM, Abdel Fattah NSA, TantawySMA (2013) Neodymium-yttrium aluminum garnet laser versus pulsed dye laser in erythemato-telangiectatic rosacea: comparison of clinical efficacy and effect on cutaneous substance (P) expression.J Cosmet Dermatol12:187–194.

124 SaundersCI, Fassett RG, GeraghtyDP (2009) Up-regulation of TRPV1 in mononuclear cells of end-stage kidney disease patients increases susceptibility to N-arachidonoyl-dopamine (NADA)-induced cell death.Biochim Biophys Acta1792:1019–1026.

125 SenningEN, Collins MD, StratiievskaA (2014) Regulation of TRPV1 ion channel by phosphoinositide (4,5)-bisphosphate: the role of membrane asymmetry.J Biol Chem289:10999–11006.

126 SereflicanB, Goksugur N, BugdayciG (2016) Serum Visfatin, Adiponectin, and Tumor Necrosis Factor Alpha (TNF-α) Levels in Patients with Psoriasis and their Correlation with Disease Severity.Acta Dermatovenerol Croat ADC24:13–19

127 ShimW-S, TakM-H, LeeM-H (2007) TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase.J Neurosci Off J Soc Neurosci27:2331–2337.

128 SilvaCR, Oliveira SM, RossatoMF (2011) The involvement of TRPA1 channel activation in the inflammatory response evoked by topical application of cinnamaldehyde to mice.Life Sci88:1077–1087.

129 SmartD, Gunthorpe MJ, JermanJC (2000) The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1).Br J Pharmacol129:227–230.

130 SmolyannikovaVA, Kubanova AA, KaramovaAE (2015) Role of the skin expression of neuropeptides, neurotrophins and their receptors in the pathogenesis of dermatoses.Arkh Patol77:33–39

131 SonkolyE, MullerA, LauermaAI (2006) IL-31: a new link between T cells and pruritus in atopic skin inflammation.J Allergy Clin Immunol117:411–417.

132 SouthallMD, LiT, GharibovaLS (2003) Activation of epidermal vanilloid receptor-1 induces release of proinflammatory mediators in human keratinocytes.J Pharmacol Exp Ther304:217–222.

133 SpahnV, SteinC, ZöllnerC (2014) Modulation of transient receptor vanilloid 1 activity by transient receptor potential ankyrin 1.Mol Pharmacol85:335–344.

134 StänderS, Moormann C, SchumacherM (2004) Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures.Exp Dermatol13:129–139.

135 StaruschenkoA, JeskeNA, AkopianAN (2010) Contribution of TRPV1-TRPA1 interaction to the single channel properties of the TRPA1 channel.J Biol Chem285:15167–15177.

136 SteinhoffM, Neisius U, IkomaA (2003) Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin.J Neurosci Off J Soc Neurosci23:6176–6180

137 StoryGM, PeierAM, ReeveAJ (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures.Cell112:819–829

138 SugiuraT, Tominaga M, KatsuyaH , MizumuraK (2002) Bradykinin lowers the threshold temperature for heat activation of vanilloid receptor 1.J Neurophysiol88:544–548

139 SuraL, Zíma V, MarsakovaL (2012) C-terminal Acidic cluster is involved in Ca2+-induced regulation of human transient receptor potential Ankyrin 1 channel.J Biol Chem287:18067–18077.

140 SzallasiA, Blumberg PM (1989) Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper.Neuroscience30:515–520

141 Taylor-ClarkTE, UndemBJ, MacglashanDW (2008) Prostaglandin-induced activation of nociceptive neurons via direct interaction with transient receptor potential A1 (TRPA1).Mol Pharmacol73:274–281.

142 Taylor-ClarkTE, GhattaS, BettnerW, Undem BJ (2009) Nitrooleic acid, an endogenous product of nitrative stress, activates nociceptive sensory nerves via the direct activation of TRPA1.Mol Pharmacol75:820–829.

143 Teresiak-MikołajczakE , Czarnecka-OperaczM, Jenerowicz D, SilnyW (2013) Neurogenic markers of the inflammatory process in atopic dermatitis: relation to the severity and pruritus.Postȩpy Dermatol Alergol30:286–292.

144 ThornePS, HawkC, KaliszewskiSD , GuineyPD (1991) The noninvasive mouse ear swelling assay. II. Testing the contact sensitizing potency of fragrances.Fundam Appl Toxicol Off J Soc Toxicol17:807–820

145 TominagaM, Caterina MJ, MalmbergAB (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli.Neuron21:531–543

146 TominagaM, WadaM, MasuM (2001) Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATP-evoked pain and hyperalgesia.Proc Natl Acad Sci U S A98:6951–6956.

147 TrevisaniM, Siemens J, MaterazziS (2007) 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1.Proc Natl Acad Sci U S A104:13519–13524.

148 Ufret-VincentyCA, Klein RM, CollinsMD (2015) Mechanism for phosphoinositide selectivity and activation of TRPV1 ion channels.J Gen Physiol145:431–442.

149 VellaniV, Mapplebeck S, MoriondoA (2001) Protein kinase C activation potentiates gating of the vanilloid receptor VR1 by capsaicin, protons, heat and anandamide.J Physiol534:813–825

150 VellaniV, KinseyAM, PrandiniM (2010) Protease activated receptors 1 and 4 sensitize TRPV1 in nociceptive neurones.Mol Pain6:61.

151 VincentL, VangD, NguyenJ (2013) Mast cell activation contributes to sickle cell pathobiology and pain in mice.Blood122:1853–1862.

152 WangS, DaiY, FukuokaT (2008a) Phospholipase C and protein kinase A mediate bradykinin sensitization of TRPA1: a molecular mechanism of inflammatory pain.Brain J Neurol131:1241–1251.

153 WangYY, ChangRB, WatersHN (2008b) The nociceptor ion channel TRPA1 is potentiated and inactivated by permeating calcium ions.J Biol Chem283:32691–32703.

154 WeiH, Koivisto A, PertovaaraA (2010) Spinal TRPA1 ion channels contribute to cutaneous neurogenic inflammation in the rat.Neurosci Lett479:253–256.

155 WeiT, GuoT-Z, LiW-W (2012) Keratinocyte expression of inflammatory mediators plays a crucial role in substance P-induced acute and chronic pain.J Neuroinflammation9:181.

156 WilsonSR, Bautista DM (2014) Role of transient receptor potential channels in acute and chronic itch.In: Carstens E, Akiyama T (eds) Itch: mechanisms and treatment. CRC Press, Boca Raton (FL)

157 WilsonSR, Gerhold KA, Bifolck-FisherA (2011) TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch.Nat Neurosci14:595–602.

158 WilsonSR, NelsonAM, BatiaL (2013a) The ion channel TRPA1 is required for chronic itch.J Neurosci Off J Soc Neurosci33:9283–9294.

159 WilsonSR, Thé L, BatiaLM (2013b) The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch.Cell155:285–295.

160 WooDH, JungSJ, ZhuMH (2008) Direct activation of transient receptor potential vanilloid 1(TRPV1) by diacylglycerol (DAG).Mol Pain4:42.

161 XieZ (2009) [Role of thermo TRP channels in cutaneous neurogenic inflammation and itch].Zhejiang Xue Xue Bao Yi Xue Ban J Zhejiang Univ Med Sci38:409–414

162 YangD, LuoZ, MaS (2010) Activation of TRPV1 by dietary capsaicin improves endothelium-dependent vasorelaxation and prevents hypertension.Cell Metab12:130–141.

163 YeF, DengP-Y, LiD (2007) Involvement of endothelial cellderived CGRP in heat stress-induced protection of endothelial function.Vascul Pharmacol46:238–246.

164 YusufN, NastiTH, HuangC-M (2009) Heat shock proteins HSP27 and HSP70 are present in the skin and are important mediators of allergic contact hypersensitivity.J Immunol Baltim Md 1950182:675–683

165 ZhangN, InanS, CowanA (2005) A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1.Proc Natl Acad Sci U S A102:4536–4541.

166 ZhangX, LiL, McNaughtonPA (2008) Proinflammatory mediators modulate the heat-activated ion channel TRPV1 via the scaffolding protein AKAP79/150.Neuron59:450–461.

167 ZhaoP, LieuT, BarlowN (2014) Cathepsin S causes inflammatory pain via biased agonism of PAR2 and TRPV4.J Biol Chem.

168 ZhaoY, BaoL, ChanLS (2016) Aberrant wound healing in an epidermal interleukin-4 transgenic mouse model of atopic dermatitis.PLoS ONE.

169 ZieglerSF, RoanF, BellBD (2013) The biology of thymic stromal lymphopoietin (TSLP).Adv Pharmacol San Diego Calif66:129–155.

170 ZupancGK (1996) Peptidergic transmission: from morphological correlates to functional implications.Micron Oxf Engl1993 (27):35–91

171 ZurborgS, Yurgionas B, JiraJA (2007) Direct activation of the ion channel TRPA1 by Ca2+.Nat Neurosci10:277–279.

172 ZygmuntPM, Petersson J, AnderssonDA (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide.Nature400:452–457.