Danger- and pathogen-associated molecular patterns recognition by pattern-recognition receptors and ion channels of the transient receptor potential family triggers the inflammasome activation in immune cells and sensory neurons

Journal of Neuroinflammation

Consuelo Amantini²  Massimo Nabissi¹  Matteo Santoni⁴  Maria Beatrice Morelli³  Claudio Cardinali³  Giorgio Santoni¹ 

[1] School of Pharmacy, Section of Experimental Medicine, University of Camerino, Camerino 62032, Italy;School of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032, Italy;Department of Molecular Medicine, Sapienza University, Rome 00185, Italy;Department of Medical Oncology, AOU Ospedali Riuniti, Polytechnic University of Marche, Ancona 60126, Italy

关键词: TRP channels;    Ion channels;    TLRs;    PRRs;    DAMPs;    PAMPs;    Caspase-1;    IL-1β;    Inflammasome;    Innate immunity;   

Others  :  1149675
DOI  :  10.1186/s12974-015-0239-2

 received in 2014-07-25, accepted in 2015-01-07,  发布年份 2015

【 摘 要 】

An increasing number of studies show that the activation of the innate immune system and inflammatory mechanisms play an important role in the pathogenesis of numerous diseases. The innate immune system is present in almost all multicellular organisms and its activation occurs in response to pathogens or tissue injury via pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Intracellular pathways, linking immune and inflammatory response to ion channel expression and function, have been recently identified. Among ion channels, the transient receptor potential (TRP) channels are a major family of non-selective cation-permeable channels that function as polymodal cellular sensors involved in many physiological and pathological processes.

In this review, we summarize current knowledge of interactions between immune cells and PRRs and ion channels of TRP families with PAMPs and DAMPs to provide new insights into the pathogenesis of inflammatory diseases. TRP channels have been found to interfere with innate immunity via both nuclear factor-kB and procaspase-1 activation to generate the mature caspase-1 that cleaves pro-interleukin-1β cytokine into the mature interleukin-1β.

Sensory neurons are also adapted to recognize dangers by virtue of their sensitivity to intense mechanical, thermal and irritant chemical stimuli. As immune cells, they possess many of the same molecular recognition pathways for danger. Thus, they express PRRs including Toll-like receptors 3, 4, 7, and 9, and stimulation by Toll-like receptor ligands leads to induction of inward currents and sensitization in TRPs. In addition, the expression of inflammasomes in neurons and the involvement of TRPs in central nervous system diseases strongly support a role of TRPs in inflammasome-mediated neurodegenerative pathologies. This field is still at its beginning and further studies may be required.

Overall, these studies highlight the therapeutic potential of targeting the inflammasomes in proinflammatory, autoinflammatory and metabolic disorders associated with undesirable activation of the inflammasome by using specific TRP antagonists, anti-human TRP monoclonal antibody or different molecules able to abrogate the TRP channel-mediated inflammatory signals.

【 授权许可】

   
2015 Santoni et al.; licensee BioMed Central.

【 参考文献 】

• [1]Fukata M, Vamadevan AS, Abreu MT: Toll-like receptors(TLRs) and Nod-like receptors (NLRs) in inflammatory disorders. Semin Immunol. 2009, 21:242-53.
• [2]Lamkanfi M, Dixit VM: Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol. 2012, 28:137-61.
• [3]Takeuchi O, Akira S: Pattern recognition receptors and inflammation. Cell. 2010, 140:805-20.
• [4]Carneiro LA, Magalhaes JG, Tattoli I, Philpott DJ, Travassos LH: Nod-like proteins in inflammation and disease. J Pathol. 2008, 214:136-48.
• [5]Kawai T, Akira S: The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010, 11:373-84.
• [6]Brown J, Wang H, Hajishengallis GN, Martin M: TLR-signaling networks: an integration of adaptor molecules, kinases, and cross-talk. J Dent Res. 2011, 90:417-27.
• [7]Jacobs SR, Damania B: NLRs, inflammasomes, and viral infection. J Leukoc Biol. 2012, 92:469-77.
• [8]Blasius AL, Beutler B: Intracellular toll-like receptors. Immunity. 2010, 32:305-15.
• [9]Schorder K, Tschopp J: The inflammasomes. Cell. 2010, 140:821-32.
• [10]Inohara C, McDonald C, Nuñez G: NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu Rev Biochem. 2005, 74:355-83.
• [11]Strowig T, Henao-Mejia J, Elinav E, Flavell R: Inflammasomes in health and disease. Nature. 2012, 481:278-86.
• [12]Wilson SP, Cassel SL: Inflammasome-mediated autoinflammatory disorders. Postgrad Med. 2010, 122:125-33.
• [13]Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR, Tephly LA, et al.: The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci U S A. 2008, 105:9035-40.
• [14]Pétrilli V, Dostert C, Muruve DA, Tschopp J: The inflammasome: a danger sensing complex triggering innate immunity. Curr Opin Immunol. 2007, 19:615-22.
• [15]Sorbara MT, Girardin SE: Mitochondrial ROS fuel the inflammasome. Cell Res. 2011, 21:558-60.
• [16]Gross O, Thomas CJ, Guarda G, Tschopp J: The inflammasome: an integrated view. Immunol Rev. 2011, 243:136-51.
• [17]Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al.: The NLRP3 inflammasome instigated obesity-induced inflammation and insulin resistance. Nat Med. 2011, 17:179-88.
• [18]Grundmann S, Bode C, Moser M: Inflammasome activation in reperfusion injury: friendly fire on myocardial infarction? Circulation. 2011, 123:574-6.
• [19]Mathew A, Lindsley TA, Sheridan A, Bhoiwala DL, Hushmendy SF, Yager EJ, et al.: Degraded mitochondrial DNA is a newly identified subtype of the damage associated molecular pattern (DAMP) family and possible trigger of neurodegeneration. J Alzheimers Dis. 2012, 30:617-27.
• [20]White JP, Urban L, Nagy I: TRPV1 function in health and disease. Curr Pharm Biotechnol. 2011, 12:130-44.
• [21]Nilius B, Owsianik G: The transient receptor potential family of ion channels. Genome Biol. 2011, 12:218.
• [22]Santoni G, Farfariello V, Amantini C: TRPV channels in tumor growth and progression. Adv Exp Med Biol. 2011, 704:947-67.
• [23]Nilius B, Owsianik G: Transient receptor potential channelopathies. Pflugers Arch. 2010, 460:437-50.
• [24]Vennekens R: Emerging concepts for the role of TRP channels in the cardiovascular system. J Physiol. 2011, 589:1527-34.
• [25]Kim H, Kim J, Jeon J, Myeong J, Wie J, Hong C, et al.: The roles of G proteins in the activation of TRPC4 and TRPC5 transient receptor potential channels. Channels (Austin). 2012, 6:333-43.
• [26]Reiser J, Polu KR, Möller CC, Kenlan P, Altintas MM, Wei C, et al.: TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet. 2005, 37:739-44.
• [27]Onohara N, Nishida M, Inoue R, Kobayashi H, Sumimoto H, Sato Y, et al.: TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy. EMBO J. 2006, 25:5305-16.
• [28]Wang P, Liu D, Tepel M, Zhu Z: Transient receptor potential canonical type 3 channels - their evolving role in hypertension and its related complications. J Cardiovasc Pharmacol. 2013, 61:455-60.
• [29]Wang D, Li X, Liu J, Li J, Li LJ, Qiu MX: Effects of TRPC6 on invasibility of low-differentiated prostate cancer cells. Asian Pac J Trop Med. 2014, 7:44-7.
• [30]Woudenberg-Vrenken TE, Bindels RJ, Hoenderop JG: The role of transient receptor potential channels in kidney disease. Nat Rev Nephrol. 2009, 5:441-9.
• [31]Holzer P, Izzo AA: The pharmacology of TRP channels. Br J Pharmacol. 2014, 171:2469-73.
• [32]Amantini C, Mosca M, Nabissi M, Lucciarini R, Caprodossi S, Arcella A, et al.: Capsaicin-induced apoptosis of glioma cells is mediated by TRPV1 vanilloid receptor and requires p38 MAPK activation. J Neurochem. 2007, 102:977-90.
• [33]Caprodossi S, Amantini C, Nabissi M, Morelli MB, Farfariello V, Santoni M, et al.: Capsaicin promotes a more aggressive gene expression phenotype and invasiveness in null-TRPV1 urothelial cancer cells. Carcinogenesis. 2011, 32:686-94.
• [34]Chubanov V, Waldegger S: Mederos y Schnitzler M, Vitzthum H, Sassen MC, Seyberth HW, Konrad M, Gudermann T. Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia. Proc Natl Acad Sci U S A. 2004, 101:2894-9.
• [35]Zheng J: Molecular mechanism of TRP Channels. Compr Physiol. 2013, 3:221-42.
• [36]Tsiokas L: Function and regulation of TRPP2 at the plasma membrane. Am J Physiol Renal Physiol. 2009, 297:F1-9.
• [37]Lapointe TK, Altier C: The role of TRPA1 in visceral inflammation and pain. Channels (Austin). 2011, 5:525-9.
• [38]Clapham DE: TRP channels as cellular sensors. Nature. 2003, 426:517-24.
• [39]Rajamäki K, Nordström T, Nurmi K, Åkerman KE, Kovanen PT, Öörni K, et al.: Extracellular acidosis is a novel danger signal alerting innate immunity via the NLRP3 inflammasome. J Biol Chem. 2013, 288:13410-9.
• [40]Chung S, Kim YH, Koh JY, Nam TS, Ahn DS: Intracellular acidification evoked by moderate extracellular acidosis attenuates transient receptor potential V1 (TRPV1) channel activity in rat dorsal root ganglion neurons. Exp Physiol. 2011, 96:1270-81.
• [41]Madrid R, Donovan-Rodríguez T, Meseguer V, Acosta MC, Belmonte C, Viana F: Contribution of TRPM8 channels to cold transduction in primary sensory neurons and peripheral nerve terminals. J Neurosci. 2006, 26:12512-25.
• [42]Wu SN, Wu PY, Tsai ML: Characterization of TRPM8-like channels activated by the cooling agent icilin in the macrophage cell line RAW 264.7. J Membr Biol. 2011, 241:11-20.
• [43]Sabnis AS, Reilly CA, Veranth JM, Yost GS: Increased transcription of cytokine genes in human lung epithelial cells through activation of a TRPM8 variant by cold temperature. Am J Physiol Lung Cell Mol Physiol. 2008, 295:194-200.
• [44]Stoffels M, Remijn T, Elders LM, de Koning HD, van der Meer JW, Simon A: A role for thermo-TRP channels in innate immunity? [abstract]. Pediatric Rheumatol. 2013, 11 Suppl 1:A176.
• [45]Yamamoto S, Shimizu S, Kiyonaka S, Takahashi N, Wajima T, Hara Y, et al.: TRPM2-mediated Ca2+influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nat Med. 2008, 14:738-47.
• [46]Hecquet CM, Malik AB: Role of H(2)O(2)-activated TRPM2 calcium channel in oxidant-induced endothelial injury. Thromb Haemost. 2009, 101:619-25.
• [47]Knowles H, Heizer JW, Li Y, Chapman K, Ogden CA, Andreasen K, et al.: Transient Receptor Potential Melastatin 2 (TRPM2) ion channels is required for innate immunity against Listeria monocytogenes. Proc Natl Acad Sci U S A. 2011, 108:11578-83.
• [48]Kim S, Bauernfeind F, Ablasser A, Hartmann G, Fitzgerald KA, Latz E, et al.: Listeria monocytogenes is sensed by the NLRP3 and AIM2 inflammasome. Eur J Immunol. 2010, 40:1545-51.
• [49]Zhou R, Yazdi AS, Menu P, Tschopp J: A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011, 469:221-5.
• [50]Murakami T, Ockinger J, Yu J, Byles V, McColl A, Hofer AM, et al.: Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci U S A. 2012, 109:11282-7.
• [51]Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, et al.: Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011, 12:222-30.
• [52]Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, et al.: Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012, 36:401-14.
• [53]Cruz-Orengo L, Dhaka A, Heuermann RJ, Young TJ, Montana MC, Cavanaugh EJ, et al.: Cutaneous nociception evoked by 15-delta PGJ2 via activation of ion channel TRPA1. Mol Pain. 2008, 4:30.
• [54]Trevisani M, Siemens J, Materazzi S, Bautista DM, Nassini R, Campi B, et al.: 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A. 2007, 104:13519-24.
• [55]Hoffmann EK, Lambert IH, Pedersen SF: Physiology of cell volume regulation in vertebrates. Physiol Rev. 2009, 89:193-277.
• [56]Lang F, Lepple-Wienhues A, Szabó I, Siemen D, Gulbins E: Cell volume in cell proliferation and apoptotic cell death. Contrib Nephrol. 1998, 123:158-68.
• [57]Newman PJ, Grana WA: The changes in human synovial fluid osmolality associated with traumatic or mechanical abnormalities of the knee. Arthroscopy. 1988, 4:179-81.
• [58]Perregaux DG, Laliberte RE, Gabel CA: Human monocyte interleukin-1beta posttranslational processing. Evidence of a volume-regulated response. J Biol Chem 1996, 271:29830-8.
• [59]Schorn C, Frey B, Lauber K, Janko C, Strysio M, Keppeler H, et al.: Sodium overload and water influx activate the NALP3 inflammasome. J Biol Chem. 2011, 286:35-41.
• [60]Compan V, Baroja-Mazo A, Lopez-Castejon G, Gomez AI, Bazan E, Reimers D, et al.: Cell volume regulation modulates NLRP3 inflammasome activation. Immunity. 2012, 37:487-500.
• [61]Liedtke W: Transient receptor potential vanilloid channels functioning in transduction of osmotic stimuli. J Endocrinol. 2006, 191:515-23.
• [62]Muraki K, Iwata Y, Katanosaka Y, Ito T, Ohya S, Shigekawa M, et al.: TRPV2 is a component of osmotically sensitive cation channels in murine aortic myocytes. Circ Res. 2003, 93:829-38.
• [63]Numata T, Shimizu T, Okada Y: TRPM7 is a stretch- and swelling-activated cation channel involved in volume regulation in human epithelial cells. Am J Physiol Cell Physiol. 2007, 292:C460-7.
• [64]Penner R, Fleig A: The Mg2+ and Mg(2+)-nucleotide-regulated channel-kinase TRPM7. Handb Exp Pharmacol. 2007, 179:313-28.
• [65]Sakurai H, Miyoshi H, Mizukami J, Sugita T: Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1. FEBS Lett. 2000, 474:141-5.
• [66]Fukuno N, Matsui H, Kanda Y, Suzuki O, Matsumoto K, Sasaki K, et al.: TGF-β-activated kinase 1 mediates mechanical stress-induced IL-6 expression in osteoblasts. Biochem Biophys Res Commun. 2011, 408:202-7.
• [67]Gong YN, Wang X, Wang J, Yang Z, Li S, Yang J, et al.: Chemical probing reveals insights into the signaling mechanism of inflammasome activation. Cell Res. 2010, 20:1289-305.
• [68]Togo T, Alderton JM, Steinhardt RA: The mechanism of cell membrane repair. Zygote. 2000, 8:S31-2.
• [69]Link TM, Park U, Vonakis BM, Raben DM, Soloski MJ, Caterina MJ: TRPV2 has a pivotal role in macrophage particle binding and phagocytosis. Nat Immunol. 2010, 11:232-9.
• [70]Tauseef M, Knezevic N, Chava KR, Smith M, Sukriti S, Gianaris N, et al.: TLR4 activation of TRPC6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation. J Exp Med. 2012, 209:1953-68.
• [71]Yamashiro K, Sasano T, Tojo K, Namekata I, Kurokawa J, Sawada N, et al.: Role of transient receptor potential vanilloid 2 in LPS-induced cytokine production in macrophages. Biochem Biophys Res Commun. 2010, 398:284-9.
• [72]Becerra A, Echeverría C, Varela D, Sarmiento D, Armisén R, Nuñez-Villena F, et al.: Transient receptor potential melastatin 4 inhibition prevents lipopolysaccharide-induced endothelial cell death. Cardiovasc Res. 2011, 91:677-84.
• [73]Darveau RP. Porphyromonas gingivalis neutrophil manipulation: risk factor for periodontitis?. Trends Microbiol. in press.
• [74]Taxman DJ, Swanson KV, Broglie PM, Wen H, Holley-Guthrie E, Huang MT, et al.: Porphyromonas gingivalis mediates inflammasome repression in polymicrobial cultures through a novel mechanism involving reduced endocytosis. J Biol Chem. 2012, 287:32791-9.
• [75]Ozturk A, Yildiz L: Expression of transient receptor potential vanilloid receptor 1 and toll-like receptor 4 in aggressive periodontitis and in chronic periodontitis. J Periodontal Res. 2011, 46:475-82.
• [76]Abdullah H, Heaney LG, Cosby SL, McGarvey LPA: Rhinovirus upregulates transient receptor potential channels in a human neuronal cell line: implications for respiratory virus-induced cough reflex sensitivity. Thorax. 2013, 69:46-54.
• [77]Chiu IM, von Hehn CA, Woolf CJ: Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat Neurosci. 2012, 15:1063-7.
• [78]Fryer AD, Stein LH, Nie Z, Curtis DE, Evans CM, Hodgson ST, et al.: Neuronal eotaxin and the effects of CCR3 antagonist on airway hyperreactivity and M2 receptor dysfunction. J Clin Invest. 2006, 116:228-36.
• [79]Ansel JC, Brown JR, Payan DG, Brown MA: Substance P selectively activates TNF-alpha gene expression in murine mast cells. J Immunol. 1993, 150:4478-85.
• [80]Ding W, Stohl LL, Wagner JA, Granstein RD: Calcitonin gene-related peptide biases Langerhans cells toward Th2-type immunity. J Immunol. 2008, 181:6020-6.
• [81]Cyphert JM, Kovarova M, Allen IC, Hartney JM, Murphy DL, Wess J, et al.: Cooperation between mast cells and neurons is essential for antigen-mediated bronchoconstriction. J Immunol. 2009, 182:7430-9.
• [82]Li WW, Guo TZ, Liang D, Shi X, Wei T, Kingery WS, et al.: The NALP1 inflammasome controls cytokine production and nociception in a rat fracture model of complex regional pain syndrome. Pain. 2009, 147:277-86.
• [83]Veres TZ, Rochlitzer S, Shevchenko M, Fuchs B, Prenzler F, Nassenstein C, et al.: Spatial interactions between dendritic cells and sensory nerves in allergic airway inflammation. Am J Respir Cell Mol Biol. 2007, 37:553-61.
• [84]Binshtok AM, Wang H, Zimmermann K, Amaya F, Vardeh D, Shi L, et al.: Nociceptors are interleukin-1beta sensors. J Neurosci. 2008, 28:14062-73.
• [85]Zhang XC, Kainz V, Burstein R, Levy D: Tumor necrosis factor-α induces sensitization of meningeal nociceptors mediated via local COX and p38 MAP kinase actions. Pain. 2011, 152:140-9.
• [86]Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, et al.: Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature. 2001, 410:471-5.
• [87]Liu T, Xu ZZ, Park CK, Berta T, Ji RR: Toll-like receptor 7 mediates pruritus. Nat Neurosci. 2010, 13:1460-2.
• [88]Diogenes A, Ferraz CC, Akioian AN, Henry MA, Hargreavest KM: LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons. J Dent Res. 2011, 90:759-64.
• [89]Qi J, Buzas K, Fan H, Cohen JI, Wang K, Mont E, et al.: Painful pathways induced by TLR stimulation of dorsal root ganglion neurons. J Immunol. 2011, 186:6417-26.
• [90]Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T, Antal A, et al.: A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1. J Allergy Clin Immunol. 2014, 133:448-60.
• [91]Park CK, Xu ZZ, Berta T, Han Q, Chen G, Liu XJ, et al.: Extracellular microRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1. Neuron. 2014, 82:47-54.
• [92]Min H, Lee H, Lim H, Jang YH, Chung SJ, Lee CJ, et al.: TLR4 enhances histamine-mediated pruritus by potentiating TRPV1 activity. Mol Brain. 2014, 7:59.
• [93]Ferraz CC, Henry MA, Hargreaves KM, Diogenes A: Lipopolysaccharide from Porphyromonas gingivalis sensitizes capsaicin-sensitive nociceptors. J Endod. 2011, 37:45-8.
• [94]Park E, Na HS, Song YR, Shin SY, Kim YM, Chung J: Activation of NLRP3 and AIM2 inflammasomes by Porphyromonas gingivalis infection. Infect Immun 2014, 82:112-23.
• [95]de Rivero Vaccari JP, Lotocki G, Marcillo AE, Dietrich WD, Keane RW: A molecular platform in neurons regulates inflammation after spinal cord injury. J Neurosci. 2008, 28:3404-14.
• [96]Cockayne DA, Hamilton SG, Zhu QM, Dunn PM, Zhong Y, Novakovic S, et al.: Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature. 2000, 407:1011-5.
• [97]Souslova V, Cesare P, Ding Y, Akopian AN, Stanfa L, Suzuki R, et al.: Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature. 2000, 407:1015-7.
• [98]Lakshmi S, Joshi PG: Co-activation of P2Y2 receptor and TRPV channel by ATP: implications for ATP induced pain. Cell Mol Neurobiol. 2005, 25:819-32.
• [99]Mariathasan S, Weiss DS, Newton K, McBride J, O'Rourke K, Roose-Girma M, et al.: Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006, 440:228-32.
• [100]Trevisan G, Hoffmeister C, Rossato MF, Oliveira SM, Silva MA, Ineu RP, et al.: Transient receptor potential ankyrin 1 receptor stimulation by hydrogen peroxide is critical to trigger pain during monosodium urate-induced inflammation in rodents. Arthritis Rheum. 2013, 65:2984-95.
• [101]Hoffmeister C, Silva MA, Rossato MF, Trevisan G, Oliveira SM, Guerra GP, et al.: Participation of the TRPV1 receptor in the development of acute gout attacks. Rheumatology (Oxford). 2014, 53:240-9.
• [102]Andersson DA, Gentry C, Bevan S: TRPA1 has a key role in the somatic pro-nociceptive actions of hydrogen sulfide. PLoS One. 2012, 7:e46917.
• [103]Zhang Z, Xu X, Ma J, Wu J, Wang Y, Zhou R, et al.: Gene deletion of Gabarap enhances Nlrp3 inflammasome-dependent inflammatory responses. J Immunol. 2013, 190:3517-24.
• [104]Kummer JA, Broekhuizen R, Everett H, Agostini L, Kuijk L, Martinon F, et al.: 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, 55:443-52.
• [105]Ramos HJ, Lanteri MC, Blahnik G, Negash A, Suthar MS, Brassil MM, et al.: IL-1β signaling promotes CNS-intrinsic immune control of West Nile virus infection. PLoS Pathog. 2012, 8:e1003039.
• [106]Karatas H, Erdener SE, Gursoy-Ozdemir Y, Lule S, Eren-Koçak E, Sen ZD, et al.: Spreading depression triggers headache by activating neuronal Panx1 channels. Science. 2013, 339:1092-5.
• [107]Minkiewicz J, de Rivero Vaccari JP, Keane RW: Human astrocytes express a novel NLRP2 inflammasome. Glia. 2013, 61:1113-21.
• [108]Walsh JG, Muruve DA, Power C: Inflammasomes in the CNS. Nat Rev Neurosci. 2014, 15:84-97.
• [109]Allan SM: Pragmatic target discovery from novel gene to functionally defined drug target: the interleukin-1 story. Methods Mol Med. 2005, 104:333-46.
• [110]Alboni S, Cervia D, Sugama S, Conti B: Interleukin 18 in the CNS. J Neuroinflammation. 2010, 7:9.
• [111]Morelli MB, Amantini C, Liberati S, Santoni M, Nabissi M: New potential therapeutic approaches in CNS neuropathies. CNS Neurol Disord Drug Targets. 2013, 12:274-93.
• [112]Takada Y, Numata T, Mori Y: Targeting TRPs in neurodegenerative disorders. Curr Top Med Chem. 2013, 13:322-34.
• [113]Hermosura MC, Garruto RM: TRPM7 and TRPM2 – candidate susceptibility genes for Western Pacific ALS and PD? Biochim Biophys Acta. 2007, 1772:822-35.
• [114]Riccio A, Medhurst AD, Mattei C, Kelsell RE, Calver AR, Randall AD, et al.: mRNA distribution analysis of human TRPC family in CNS and peripheral tissues. Brain Res Mol Brain Res. 2002, 109:95-104.
• [115]Tozzi A, Bengtson CP, Longone P, Carignani C, Fusco FR, Bernardi G, et al.: Involvement of transient receptor potential-like channels in responses to mGluR-I activation in midbrain dopamine neurons. Eur J Neurosci. 2003, 18:2133-45.
• [116]de Lago E, de Miguel R, Lastres-Becker I, Ramos JA, Fernandez-Ruiz J: Involvement of vanilloid-like receptors in the effects of anandamide on motor behavior and nigrostriatal dopaminergic activity: in vivo and in vitro evidence. Brain Res. 2004, 1007:152-9.
• [117]Yamamoto S, Wajima T, Hara Y, Nishida M, Mori Y: Transient receptor potential channels in Alzheimer’s disease. Biochim Biophys Acta. 2007, 1772:958-67.
• [118]Lendman N, Jeong SY, Shin SY, Voronov SV, Serban G, Kang MS, et al.: Presenilin mutations linked to familial Alzheimer’sdisease cause an imbalance in phosphatidylinositol 4,5-biphosphate metabolism. Proc Natl Acad Sci U S A. 2006, 103:19524-9.
• [119]Lessard CB, Lussier MP, Cayouette S, Bourque G, Boulay G: The overexpression of presenilin2 and Alzheimer's-disease-linked presenilin-2 variants influences TRPC6-enhanced Ca2+ entry into HEK293 cells. Cell Signal. 2005, 17:437-45.
• [120]Fonfria E, Marshall IC, Boyfield I, Skaper SD, Hughes JP, Owen DE, et al.: Amyloid beta-peptide(1–42) and hydrogen peroxide-induced toxicity are mediated by TRPM2 in rat primary striatal cultures. Neurochemistry. 2005, 95:715-23.
• [121]Inoue K, Branigan D, Xiong ZG: Zinc-induced neurotoxicity mediated by transient receptor potential melastatin 7 channels. J Biol Chem. 2010, 285:7430-9.
• [122]Weilinger NL, Maslieieva V, Bialecki J, Sridharan SS, Tang PL, Thompson RJ: Ionotropic receptors and ion channels in ischemic neuronal death and dysfunction. Acta Pharmacol Sin. 2013, 34:39-48.
• [123]Ting JPY, Willingham SB, Bergstralh DT: NLRs at the intersection of cell death and Immunity. Nature Rev Immunol. 2008, 8:372-9.
• [124]Zhong Z, Zhai Y, Liang S, Mori Y, Han R, Sutterwala FS, et al.: TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat Commun. 2013, 4:1611.
• [125]Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al.: The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008, 9:857-65.
• [126]Salminen A, Ojala J, Suuronen T, Kaarniranta K, Kaupplnen A: Amyloid-b oligomers set fire to inflammasomes and induce Alzheimer’s pathology. J Cell Mol Med. 2008, 12:2255-62.
• [127]Miller BA: The role of TRP channels in oxidative stress-induced cell death. J Membrane Biol. 2006, 209:31-41.
• [128]Papatriantafyllou M: Innate immunity: inflammasome triggered by cell swelling. Nat Rev Immunol. 2012, 12:742.
• [129]Thilo F, Scholze A, Liu DY, Zidek W, Tepel M: Association of transient receptor potential canonical type 3 (TRPC3) channel transcripts with proinflammatory cytokines. Arch Biochem Biophys. 2008, 471:57-62.