Mechanisms of Inflammasome Signaling, microRNA Induction and Resolution of Inflammation by Helicobacter pylori

  • Suneesh Kumar Pachathundikandi
  • Nicole Blaser
  • Steffen BackertEmail author
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 421)


Inflammasome-controlled transcription and subsequent cleavage-mediated activation of mature IL-1β and IL-18 cytokines exemplify a crucial innate immune mechanism to combat intruding pathogens. Helicobacter pylori represents a predominant persistent infection in humans, affecting approximately half of the population worldwide, and is associated with the development of chronic gastritis, peptic ulcer disease, and gastric cancer. Studies in knockout mice have demonstrated that the pro-inflammatory cytokine IL-1β plays a central role in gastric tumorigenesis. Infection by H. pylori was recently reported to stimulate the inflammasome both in cells of the mouse and human immune systems. Using mouse models and in vitro cultured cell systems, the bacterial pathogenicity factors and molecular mechanisms of inflammasome activation have been analyzed. On the one hand, it appears that H. pylori-stimulated IL-1β production is triggered by engagement of the immune receptors TLR2 and NLRP3, and caspase-1. On the other hand, microRNA hsa-miR-223-3p is induced by the bacteria, which controls the expression of NLRP3. This regulating effect by H. pylori on microRNA expression was also described for more than 60 additionally identified microRNAs, indicating a prominent role for inflammatory and other responses. Besides TLR2, TLR9 becomes activated by H. pylori DNA and further TLR10 stimulated by the bacteria induce the secretion of IL-8 and TNF, respectively. Interestingly, TLR-dependent pathways can accelerate both pro- and anti-inflammatory responses during H. pylori infection. Balancing from a pro-inflammation to anti-inflammation phenotype results in a reduction in immune attack, allowing H. pylori to persistently colonize and to survive in the gastric niche. In this chapter, we will pinpoint the role of H. pylori in TLR- and NLRP3 inflammasome-dependent signaling together with the differential functions of pro- and anti-inflammatory cytokines. Moreover, the impact of microRNAs on H. pylori–host interaction will be discussed, and its role in resolution of infection versus chronic infection, as well as in gastric disease development.


CagA miRNA Urease T4SS TLR2 Caspase 



This work was supported by the German Science Foundation (project A04 in CRC-1181 to S.B.).

Conflict of Interest The authors declare no conflict of interest.


  1. Allison CC, Ferrand J, McLeod L, Hassan M, Kaparakis-Liaskos M, Grubman A, Bhathal PS, Dev A, Sievert W, Jenkins BJ, Ferrero RL (2013) Nucleotide oligomerization domain 1 enhances IFN-γ signaling in gastric epithelial cells during Helicobacter pylori infection and exacerbates disease severity. J Immunol 190:3706–3715. Scholar
  2. Alvarez-Garcia I, Miska EA (2005) MicroRNA functions in animal development and human disease. Development 132:4653–4662. Scholar
  3. Amedei A, Cappon A, Codolo G, Cabrelle A, Polenghi A, Benagiano M, Tasca E, Azzurri A, D’Elios MM, Del Prete G, de Bernard M (2006) The neutrophil-activating protein of Helicobacter pylori promotes Th1 immune responses. J Clin Invest 116:1092–1101. Scholar
  4. Amieva MR, El-Omar EM (2008) Host-bacterial interactions in Helicobacter pylori infection. Gastroenterology 134:306–323. Scholar
  5. Andersen-Nissen E, Smith KD, Strobe KL, Barrett SLR, Cookson BT, Logan SM, Aderem A (2005) Evasion of Toll-like receptor 5 by flagellated bacteria. Proc Natl Acad Sci USA 102:9247–9252. Scholar
  6. Ando T, Yoshida T, Enomoto S, Asada K, Tatematsu M, Ichinose M, Sugiyama T, Ushijima T (2009) DNA methylation of microRNA genes in gastric mucosae of gastric cancer patients: its possible involvement in the formation of epigenetic field defect. Int J Cancer 124:2367–2374. Scholar
  7. Andreakos E, Foxwell B, Feldmann M (2004) Is targeting Toll-like receptors and their signaling pathway a useful therapeutic approach to modulating cytokine-driven inflammation? Immunol Rev 202:250–265. Scholar
  8. Arnold IC, Zhang X, Urban S, Artola-Borán M, Manz MG, Ottemann KM, Müller A (2017) NLRP3 controls the development of gastrointestinal CD11b+ dendritic cells in the steady state and during chronic bacterial infection. Cell Reports 21:3860–3872. Scholar
  9. Atherton JC, Blaser MJ (2009) Coadaptation of Helicobacter pylori and humans: ancient history, modern implications. J Clin Invest 119:2475–2487. Scholar
  10. Backert S, Feller SM, Wessler S (2008) Emerging roles of Abl family tyrosine kinases in microbial pathogenesis. Trends Biochem Sci 33(2):80–90. Scholar
  11. Backert S, Naumann M (2010) What a disorder: proinflammatory signaling pathways induced by Helicobacter pylori. Trends Microbiol 18:479–486. Scholar
  12. Backert S, Tegtmeyer N, Fischer W (2015) Composition, structure and function of the Helicobacter pylori cag pathogenicity island encoded type IV secretion system. Future Microbiol 10(6):955–965. Scholar
  13. Bafica A, Scanga CA, Feng CG, Leifer C, Cheever A, Sher A (2005) TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis. J Exp Med 202:1715–1724. Scholar
  14. Bansal K, Balaji KN (2011) Intracellular pathogen sensor NOD2 programs macrophages to trigger notch1 activation. J Biol Chem 286:5823–5835. Scholar
  15. Barrozo RM, Hansen LM, Lam AM, Skoog EC, Martin ME, Cai LP, Lin Y, Latoscha A, Suerbaum S, Canfield DR, Solnick JV (2016) CagY is an immune-sensitive regulator of the Helicobacter pylori type IV secretion system. Gastroenterology 151:1164–1175.e3. Scholar
  16. Basso D, Scrigner M, Toma A, Navaglia F, Di Mario F, Rugge M, Plebani M (1996) Helicobacter pylori infection enhances mucosal interleukin-1 beta, interleukin-6, and the soluble receptor of interleukin-2. Int J Clin Lab Res 26:207–210CrossRefGoogle Scholar
  17. Bauditz J, Ortner M, Bierbaum M, Niedobitek G, Lochs H, Schreiber S (1999) Production of IL-12 in gastritis relates to infection with Helicobacter pylori. Clin Exp Immunol 117:316–323CrossRefGoogle Scholar
  18. Beceiro S, Radin JN, Chatuvedi R, Piazuelo MB, Horvarth DJ, Cortado H, Gu Y, Dixon B, Gu C, Lange I, Koomoa D-L, Wilson KT, Algood HMS, Partida-Sánchez S (2017) TRPM2 ion channels regulate macrophage polarization and gastric inflammation during Helicobacter pylori infection. Mucosal Immunol 10:493–507. Scholar
  19. Beutler BA (2008) TLRs and innate immunity. Blood 113:1399–1407. Scholar
  20. Birkholz S, Knipp U, Nietzki C, Adamek RJ, Opferkuch W (1993) Immunological activity of lipopolysaccharide of Helicobacter pylori on human peripheral mononuclear blood cells in comparison to lipopolysaccharides of other intestinal bacteria. FEMS Immunol Med Microbiol 6:317–324. Scholar
  21. Bodger K, Bromelow K, Wyatt JI, Heatley RV (2001) Interleukin 10 in Helicobacter pylori associated gastritis: immunohistochemical localisation and in vitro effects on cytokine secretion. J Clin Pathol 54:285–292CrossRefGoogle Scholar
  22. Brawner KM, Kumar R, Serrano CA, Ptacek T, Lefkowitz E, Morrow CD, Zhi D, Kyanam-Kabir-Baig KR, Smythies LE, Harris PR, Smith PD (2017) Helicobacter pylori infection is associated with an altered gastric microbiota in children. Mucosal Immunol 10:1169–1177. Scholar
  23. Brisslert M, Enarsson K, Lundin S, Karlsson A, Kusters JG, Svennerholm AM, Backert S, Quiding-Järbrink M (2005) Helicobacter pylori induce neutrophil transendothelial migration: role of the bacterial HP-NAP. FEMS Microbiol Lett 249(1):95–103CrossRefGoogle Scholar
  24. Bryant CE, Spring DR, Gangloff M, Gay NJ (2010) The molecular basis of the host response to lipopolysaccharide. Nat Rev Microbiol 8:8–14. Scholar
  25. Cadamuro ACT, Rossi AFT, Maniezzo NM, Silva AE (2014) Helicobacter pylori infection: host immune response, implications on gene expression and microRNAs. World J Gastroenterol 20:1424–1437. Scholar
  26. Carbo A, Olivares-Villagómez D, Hontecillas R, Bassaganya-Riera J, Chaturvedi R, Piazuelo MB, Delgado A, Washington MK, Wilson KT, Algood HMS (2014) Systems modeling of the role of interleukin-21 in the maintenance of effector CD4+ T cell responses during chronic Helicobacter pylori infection. MBio 5:e01243–e01214. Scholar
  27. Caruso R, Fina D, Paoluzi OA, Del Vecchio Blanco G, Stolfi C, Rizzo A, Caprioli F, Sarra M, Andrei F, Fantini MC, MacDonald TT, Pallone F, Monteleone G (2008) IL-23-mediated regulation of IL-17 production in Helicobacter pylori-infected gastric mucosa. Eur J Immunol 38:470–478. Scholar
  28. Caruso R, Fina D, Peluso I, Fantini MC, Tosti C, Del Vecchio Blanco G, Paoluzi OA, Caprioli F, Andrei F, Stolfi C, Romano M, Ricci V, MacDonald TT, Pallone F, Monteleone G (2007) IL-21 is highly produced in Helicobacter pylori-infected gastric mucosa and promotes gelatinases synthesis. J Immunol 178:5957–5965CrossRefGoogle Scholar
  29. Chang H, Kim N, Park JH, Nam RH, Choi YJ, Lee HS, Yoon H, Shin CM, Park YS, Kim JM, Lee DH (2015a) Different microRNA expression levels in gastric cancer depending on Helicobacter pylori infection. Gut Liver 9:188–196. Scholar
  30. Chang H, Kim N, Park JH, Nam RH, Choi YJ, Park SM, Choi YJ, Yoon H, Shin CM, Lee DH (2015b) Helicobacter pylori might induce TGF-β1-mediated EMT by means of cagE. Helicobacter 20:438–448. Scholar
  31. Chang L-L, Wang S-W, Wu I-C, Yu F-J, Su Y-C, Chen Y-P, Wu D-C, Kuo C-H, Hung C-H (2012) Impaired dendritic cell maturation and IL-10 production following H. pylori stimulation in gastric cancer patients. Appl Microbiol Biotechnol 96:211–220. Scholar
  32. Chattoraj P, Yang Q, Khandai A, Al-Hendy O, Ismail N (2013) TLR2 and Nod2 mediate resistance or susceptibility to fatal intracellular Ehrlichia infection in murine models of ehrlichiosis. PLoS ONE 8:e58514. Scholar
  33. Chen G, Tang N, Wang C, Xiao L, Yu M, Zhao L, Cai H, Han L, Xie C, Zhang Y (2017) TNF-α-inducing protein of Helicobacter pylori induces epithelial-mesenchymal transition (EMT) in gastric cancer cells through activation of IL-6/STAT3 signaling pathway. Biochem Biophys Res Commun 484:311–317. Scholar
  34. Chen W, Shu D, Chadwick VS (2001) Helicobacter pylori infection: mechanism of colonization and functional dyspepsia Reduced colonization of gastric mucosa by Helicobacter pylori in mice deficient in interleukin-10. J Gastroenterol Hepatol 16:377–383CrossRefGoogle Scholar
  35. Cheng SF, Li L, Wang LM (2015) miR-155 and miR-146b negatively regulates IL6 in Helicobacter pylori (cagA+) infected gastroduodenal ulcer. Eur Rev Med Pharmacol Sci 19:607–613PubMedGoogle Scholar
  36. Chung J-W, Jeong SH, Lee SM, Pak JH, Lee GH, Jeong J-Y, Kim J-H (2017) Expression of microRNA in host cells infected with Helicobacter pylori. Gut Liver 11:392–400. Scholar
  37. Cook KW, Letley DP, Ingram RJM, Staples E, Skjoldmose H, Atherton JC, Robinson K (2014) CCL20/CCR6-mediated migration of regulatory T cells to the Helicobacter pylori-infected human gastric mucosa. Gut 63:1550–1559. Scholar
  38. Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, Ferguson DJP, Campbell BJ, Jewell D, Simmons A (2010) NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 16:90–97. Scholar
  39. Cortés-Márquez AC, Mendoza-Elizalde S, Arenas-Huertero F, Trillo-Tinoco J, Valencia-Mayoral P, Consuelo-Sánchez A, Zarate-Franco J, Dionicio-Avendaño AR, de Jesús Herrera-Esquivel J, Recinos-Carrera EG, Colín-Valverde C, Rivera-Gutiérrez S, Reyes-López A, Vigueras-Galindo JC, Velázquez-Guadarrama N (2018) Differential expression of miRNA-146a and miRNA-155 in gastritis induced by Helicobacter pylori infection in paediatric patients, adults, and an animal model. BMC Infect Dis 18:463. Scholar
  40. Cullen TW, Giles DK, Wolf LN, Ecobichon C, Boneca IG, Trent MS (2011) Helicobacter pylori versus the host: remodeling of the bacterial outer membrane is required for survival in the gastric mucosa. PLoS Pathog 7:e1002454. Scholar
  41. Datta C, Subuddhi A, Kumar M, Lepcha TT, Chakraborty S, Jana K, Ghosh Z, Mukhopadhyay AK, Basu J, Kundu M (2018) Genome-wide mRNA-miRNA profiling uncovers a role of the microRNA miR-29b-1-5p/PHLPP1 signalling pathway in Helicobacter pylori-driven matrix metalloproteinase production in gastric epithelial cells. Cell Microbiol 20:e12859. Scholar
  42. dela Pena-Ponce MG, Jimenez MT, Hansen LM, Solnick JV, Miller LA (2017) The Helicobacter pylori type IV secretion system promotes IL-8 synthesis in a model of pediatric airway epithelium via p 38 MAP kinase. PLOS ONE 12:e0183324.
  43. Dinarello CA (2009) Immunological and inflammatory functions of the Interleukin-1 family. Annu Rev Immunol 27:519–550. Scholar
  44. Ding H, Nedrud JG, Blanchard TG, Zagorski BM, Li G, Shiu J, Xu J, Czinn SJ (2013) Th1-mediated immunity against Helicobacter pylori can compensate for lack of Th17 cells and can protect mice in the absence of immunization. PLoS ONE 8:e69384. Scholar
  45. Dunn BE, Cohen H, Blaser MJ (1997) Helicobacter pylori. Clin Microbiol Rev 10(4):720–741CrossRefGoogle Scholar
  46. Eaton KA, Mefford ME (2001) Cure of Helicobacter pylori infection and resolution of gastritis by adoptive transfer of splenocytes in mice. Infect Immun 69:1025–1031. Scholar
  47. Eck M, Schmausser B, Scheller K, Toksoy A, Kraus M, Menzel T, Müller-Hermelink HK, Gillitzer R (2000) CXC chemokines Gro(alpha)/IL-8 and IP-10/MIG in Helicobacter pylori gastritis. Clin Exp Immunol 122:192–199CrossRefGoogle Scholar
  48. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N, Lanyon G, Martin M, Fraumeni JF, Rabkin CS (2000) Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404:398–402. Scholar
  49. El-Omar EM, Rabkin CS, Gammon MD, Vaughan TL, Risch HA, Schoenberg JB, Stanford JL, Mayne ST, Goedert J, Blot WJ, Fraumeni JF, Chow W-H (2003) Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 124:1193–1201CrossRefGoogle Scholar
  50. Engler DB, Reuter S, van Wijck Y, Urban S, Kyburz A, Maxeiner J, Martin H, Yogev N, Waisman A, Gerhard M, Cover TL, Taube C, Müller A (2014) Effective treatment of allergic airway inflammation with Helicobacter pylori immunomodulators requires BATF3-dependent dendritic cells and IL-10. Proc Natl Acad Sci USA 111:11810–11815. Scholar
  51. Fassan M, Saraggi D, Balsamo L, Cascione L, Castoro C, Coati I, De Bernard M, Farinati F, Guzzardo V, Valeri N, Zambon CF, Rugge M (2016) Let-7c down-regulation in Helicobacter pylori-related gastric carcinogenesis. Oncotarget 7:4915–4924. Scholar
  52. Ferreira RM, Pinto-Ribeiro I, Wen X, Marcos-Pinto R, Dinis-Ribeiro M, Carneiro F, Figueiredo C (2016) Helicobacter pylori cagA promoter region sequences influence CagA expression and Interleukin 8 secretion. J Infect Dis 213:669–673. Scholar
  53. Ferwerda G, Kramer M, de Jong D, Piccini A, Joosten LA, DevesaGiner I, Girardin SE, Adema GJ, van der Meer JWM, Kullberg B-J, Rubartelli A, Netea MG (2008) Engagement of NOD2 has a dual effect on proIL-1β mRNA transcription and secretion of bioactive IL-1β. Eur J Immunol 38:184–191.
  54. Franchi L, Muñoz-Planillo R, Núñez G (2012) Sensing and reacting to microbes through the inflammasomes. Nat Immunol 13:325–332. Scholar
  55. Garhart CA, Heinzel FP, Czinn SJ, Nedrud JG (2003) Vaccine-induced reduction of Helicobacter pylori colonization in mice is interleukin-12 dependent but gamma interferon and inducible nitric oxide synthase independent. Infect Immun 71:910–921CrossRefGoogle Scholar
  56. Geng Y, Lu X, Wu X, Xue L, Wang X, Xu J (2016) MicroRNA-27b suppresses Helicobacter pylori-induced gastric tumorigenesis through negatively regulating Frizzled7. Oncol Rep 35:2441–2450. Scholar
  57. Gewirtz AT, Yu Y, Krishna US, Israel DA, Lyons SL, Peek RM (2004) Helicobacter pylori flagellin evades toll-like receptor 5-mediated innate immunity. J Infect Dis 189:1914–1920. Scholar
  58. Gionchetti P, Vaira D, Campieri M, Holton J, Menegatti M, Belluzzi A, Bertinelli E, Ferretti M, Brignola C, Miglioli M (1994) Enhanced mucosal interleukin-6 and -8 in Helicobacter pylori-positive dyspeptic patients. Am J Gastroenterol 89:883–887PubMedGoogle Scholar
  59. Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, Philpott DJ, Sansonetti PJ (2003) Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 278:8869–8872. Scholar
  60. Giza DE, Vasilescu C, Calin GA (2014) Key principles of miRNA involvement in human diseases. Discoveries (Craiova) 2:e34.
  61. Gobert AP, Bambou J-C, Werts C, Balloy V, Chignard M, Moran AP, Ferrero RL (2004) Helicobacter pylori heat shock protein 60 mediates Interleukin-6 production by macrophages via a Toll-like receptor (TLR)-2-, TLR-4-, and myeloid differentiation factor 88-independent mechanism. J Biol Chem 279:245–250. Scholar
  62. Gobert AP, Verriere T, Asim M, Barry DP, Piazuelo MB, de Sablet T, Delgado AG, Bravo LE, Correa P, Peek RM Jr, Chaturvedi R, Wilson KT (2014) Heme oxygenase-1 dysregulates macrophage polarization and the immune response to Helicobacter pylori. J Immunol 193:3013–3022. Scholar
  63. Gobert AP, Wilson KT (2016) The immune battle against Helicobacter pylori infection: no offense. Trends Microbiol 24:366–376. Scholar
  64. Gringhuis SI, den Dunnen J, Litjens M, van der Vlist M, Geijtenbeek TBH (2009) Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori. Nat Immunol 10:1081–1088. Scholar
  65. Gringhuis SI, den Dunnen J, Litjens M, van het Hof B, van Kooyk Y, Geijtenbeek TBH (2007) C-type lectin DC-SIGN modulates Toll-like receptor signaling via Raf-1 Kinase-dependent acetylation of transcription factor NF-κB. Immunity 26:605–616. Scholar
  66. Gringhuis SI, Kaptein TM, Wevers BA, Mesman AW, Geijtenbeek TBH (2014) Fucose-specific DC-SIGN signalling directs T helper cell type-2 responses via IKKε- and CYLD-dependent Bcl3 activation. Nature Communications 5.
  67. Guiney DG, Hasegawa P, Cole SP (2003) Helicobacter pylori preferentially induces interleukin 12 (IL-12) rather than IL-6 or IL-10 in human dendritic cells. Infect Immun 71:4163–4166CrossRefGoogle Scholar
  68. Guo H, Callaway JB, Ting JP-Y (2015) Inflammasomes: mechanism of action, role in disease and therapeutics. Nat Med 21:677–687. Scholar
  69. Haeberle HA, Kubin M, Bamford KB, Garofalo R, Graham DY, El-Zaatari F, Karttunen R, Crowe SE, Reyes VE, Ernst PB (1997) Differential stimulation of interleukin-12 (IL-12) and IL-10 by live and killed Helicobacter pylori in vitro and association of IL-12 production with gamma interferon-producing T cells in the human gastric mucosa. Infect Immun 65:4229–4235PubMedPubMedCentralGoogle Scholar
  70. Hara H, Tsuchiya K, Kawamura I, Fang R, Hernandez-Cuellar E, Shen Y, Mizuguchi J, Schweighoffer E, Tybulewicz V, Mitsuyama M (2013) Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. Nat Immunol 14:1247–1255. Scholar
  71. Hayashi Y, Tsujii M, Wang J, Kondo J, Akasaka T, Jin Y, Li W, Nakamura T, Nishida T, Iijima H, Tsuji S, Kawano S, Hayashi N, Takehara T (2013) CagA mediates epigenetic regulation to attenuate let-7 expression in Helicobacter pylori-related carcinogenesis. Gut 62:1536–1546. Scholar
  72. Hedl M, Abraham C (2013) NLRP1 and NLRP3 inflammasomes are essential for distinct outcomes of decreased cytokines but enhanced bacterial killing upon chronic Nod2 stimulation. Am J Physiol-Gastrointest Liver Physiol 304:G583–G596.
  73. Hitkova I, Yuan G, Anderl F, Gerhard M, Kirchner T, Reu S, Röcken C, Schäfer C, Schmid RM, Vogelmann R, Ebert MPA, Burgermeister E (2013) Caveolin-1 protects B6129 mice against Helicobacter pylori gastritis. PLoS Pathog 9:e1003251. Scholar
  74. Horvath DJ, Radin JN, Cho SH, Washington MK, Algood HMS (2013) The Interleukin-17 Receptor B subunit is essential for the Th2 response to Helicobacter pylori, but not for control of bacterial burden. PLoS ONE 8:e60363. Scholar
  75. Horvath DJ, Washington MK, Cope VA, Algood HMS (2012) IL-23 contributes to control of chronic Helicobacter pylori infection and the development of T Helper responses in a mouse model. Front Immunol 3:56. Scholar
  76. Hsu L-C, Ali SR, McGillivray S, Tseng P-H, Mariathasan S, Humke EW, Eckmann L, Powell JJ, Nizet V, Dixit VM, Karin M (2008) A NOD2-NALP1 complex mediates caspase-1-dependent IL-1 secretion in response to Bacillus anthracis infection and muramyl dipeptide. Proc Natl Acad Sci 105:7803–7808. Scholar
  77. Hussain K, Letley DP, Greenaway AB, Kenefeck R, Winter JA, Tomlinson W, Rhead J, Staples E, Kaneko K, Atherton JC, Robinson K (2016) Helicobacter pylori-mediated protection from allergy is associated with IL-10-secreting peripheral blood regulatory T cells. Front Immunol 7.
  78. Ishihara S, Rumi MAK, Kadowaki Y, Ortega-Cava CF, Yuki T, Yoshino N, Miyaoka Y, Kazumori H, Ishimura N, Amano Y, Kinoshita Y (2004) Essential role of MD-2 in TLR4-dependent signaling during Helicobacter pylori-associated gastritis. J Immunol 173:1406–1416CrossRefGoogle Scholar
  79. Isomoto H, Matsushima K, Inoue N, Hayashi T, Nakayama T, Kunizaki M, Hidaka S, Nakayama M, Hisatsune J, Nakashima M, Nagayasu T, Nakao K, Hirayama T (2012) Interweaving microRNAs and proinflammatory cytokines in gastric mucosa with reference to H. pylori infection. J Clin Immunol 32:290–299. Scholar
  80. Itoh T, Yoshida M, Chiba T, Kita T, Wakatsuki Y (2003) A coordinated cytotoxic effect of IFN-gamma and cross-reactive antibodies in the pathogenesis of Helicobacter pylori gastritis. Helicobacter 8:268–278CrossRefGoogle Scholar
  81. Jo Y, Han SU, Kim YJ, Kim JH, Kim ST, Kim S-J, Hahm K-B (2010) Suppressed gastric mucosal TGF-β1 increases susceptibility to H. pylori-induced gastric inflammation and ulceration: A stupid host defense response. Gut and Liver 4:43–53. Scholar
  82. Kaebisch R, Mejías-Luque R, Prinz C, Gerhard M (2014) Helicobacter pylori cytotoxin-associated gene A impairs human dendritic cell maturation and function through IL-10-mediated activation of STAT3. J Immunol 192:316–323. Scholar
  83. Kameoka S, Kameyama T, Hayashi T, Sato S, Ohnishi N, Hayashi T, Murata-Kamiya N, Higashi H, Hatakeyama M, Takaoka A (2016) Helicobacter pylori induces IL-1β protein through the inflammasome activation in differentiated macrophagic cells. Biomed Res 37:21–27. Scholar
  84. Kandulski A, Wex T, Kuester D, Peitz U, Gebert I, Roessner A, Malfertheiner P (2008) Naturally occurring regulatory T cells (CD4+, CD25 high, FOXP3+) in the antrum and cardia are associated with higher Helicobacter pylori colonization and increased gene expression of TGF-beta1. Helicobacter 13:295–303. Scholar
  85. Kang DW, Yang ES, Noh YN, Hwang WC, Jo S-Y, Suh Y-A, Park WS, Choi K-Y, Min DS (2017) MicroRNA-320a and microRNA-4496 attenuate Helicobacter pylori cytotoxin-associated gene A (CagA)-induced cancer-initiating potential and chemoresistance by targeting β-catenin and ATP-binding cassette, subfamily G, member 2. J Pathol 241:614–625. Scholar
  86. Kao JY, Rathinavelu S, Eaton KA, Bai L, Zavros Y, Takami M, Pierzchala A, Merchant JL (2006) Helicobacter pylori-secreted factors inhibit dendritic cell IL-12 secretion: a mechanism of ineffective host defense. Am J Physiol Gastrointest Liver Physiol 291:G73–G81. Scholar
  87. Kao JY, Zhang M, Miller MJ, Mills JC, Wang B, Liu M, Eaton KA, Zou W, Berndt BE, Cole TS, Takeuchi T, Owyang SY, Luther J (2010) Helicobacter pylori immune escape is mediated by dendritic cell-induced Treg skewing and Th17 suppression in mice. Gastroenterology 138:1046–1054. Scholar
  88. Kersse K, Bertrand MJM, Lamkanfi M, Vandenabeele P (2011) NOD-like receptors and the innate immune system: Coping with danger, damage and death. Cytokine Growth Factor Rev 22:257–276. Scholar
  89. Kiga K, Mimuro H, Suzuki M, Shinozaki-Ushiku A, Kobayashi T, Sanada T, Kim M, Ogawa M, Iwasaki YW, Kayo H, Fukuda-Yuzawa Y, Yashiro M, Fukayama M, Fukao T, Sasakawa C (2014) Epigenetic silencing of miR-210 increases the proliferation of gastric epithelium during chronic Helicobacter pylori infection. Nat Commun 5:4497. Scholar
  90. Kim D-J, Park J-H, Franchi L, Backert S, Núñez G (2013) The Cag pathogenicity island and interaction between TLR2/NOD2 and NLRP3 regulate IL-1β production in Helicobacter pylori infected dendritic cells: Immunity to infection. Eur J Immunol 43:2650–2658. Scholar
  91. Kim SH, Sierra RA, McGee DJ, Zabaleta J (2012) Transcriptional profiling of gastric epithelial cells infected with wild type or arginase-deficient Helicobacter pylori. BMC Microbiol 12:175. Scholar
  92. Koch KN, Hartung ML, Urban S, Kyburz A, Bahlmann AS, Lind J, Backert S, Taube C, Müller A (2015) Helicobacter urease-induced activation of the TLR2/NLRP3/IL-18 axis protects against asthma. J Clin Invest 125:3297–3302. Scholar
  93. Koch M, Mollenkopf H-J, Klemm U, Meyer TF (2012) Induction of microRNA-155 is TLR- and type IV secretion system-dependent in macrophages and inhibits DNA-damage induced apoptosis. Proc Natl Acad Sci USA 109:E1153–E1162. Scholar
  94. Kong D, Piao Y-S, Yamashita S, Oshima H, Oguma K, Fushida S, Fujimura T, Minamoto T, Seno H, Yamada Y, Satou K, Ushijima T, Ishikawa T-O, Oshima M (2012) Inflammation-induced repression of tumor suppressor miR-7 in gastric tumor cells. Oncogene 31:3949–3960. Scholar
  95. Krauss-Etschmann S, Sammler E, Koletzko S, Konstantopoulos N, Aust D, Gebert B, Luckow B, Reinhardt D, Schendel DJ (2003) Chemokine receptor 5 expression in gastric mucosa of Helicobacter pylori-infected and noninfected children. Clin Diagn Lab Immunol 10:22–29PubMedPubMedCentralGoogle Scholar
  96. Lamkanfi M (2011) Emerging inflammasome effector mechanisms. Nat Rev Immunol 11:213–220. Scholar
  97. Latz E, Xiao TS, Stutz A (2013) Activation and regulation of the inflammasomes. Nat Rev Immunol 13:397–411. Scholar
  98. Lee JW, Kim N, Park JH, Kim HJ, Chang H, Kim JM, Kim J-W, Lee DH (2017) Differential microRNA expression between gastric cancer tissue and non-cancerous gastric mucosa according to Helicobacter pylori Status. J Cancer Prev 22:33–39.
  99. Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854CrossRefGoogle Scholar
  100. Li N, Xu X, Xiao B, Zhu E-D, Li B-S, Liu Z, Tang B, Zou Q-M, Liang H-P, Mao X-H (2012) Helicobacter pylori related proinflammatory cytokines contribute to the induction of miR-146a in human gastric epithelial cells. Mol Biol Rep 39:4655–4661. Scholar
  101. Li Z, Li J (2006) Local expressions of TGF-beta1, TGF-beta1RI, CTGF, and Smad-7 in Helicobacter pylori-associated gastritis. Scand J Gastroenterol 41:1007–1012. Scholar
  102. Lindgren A, Pavlovic V, Flach C-F, Sjöling A, Lundin S (2011) Interferon-gamma secretion is induced in IL-12 stimulated human NK cells by recognition of Helicobacter pylori or TLR2 ligands. Innate Immun 17:191–203. Scholar
  103. Liu Z, Wang D, Hu Y, Zhou G, Zhu C, Yu Q, Chi Y, Cao Y, Jia C, Zou Q (2013) MicroRNA-146a negatively regulates PTGS2 expression induced by Helicobacter pylori in human gastric epithelial cells. J Gastroenterol 48:86–92. Scholar
  104. Liu Z, Xiao B, Tang B, Li B, Li N, Zhu E, Guo G, Gu J, Zhuang Y, Liu X, Ding H, Zhao X, Guo H, Mao X, Zou Q (2010) Up-regulated microRNA-146a negatively modulate Helicobacter pylori-induced inflammatory response in human gastric epithelial cells. Microbes Infect 12:854–863. Scholar
  105. Lu H, Wu JY, Kudo T, Ohno T, Graham DY, Yamaoka Y (2005) Regulation of interleukin-6 promoter activation in gastric epithelial cells infected with Helicobacter pylori. Mol Biol Cell 16:4954–4966. Scholar
  106. Lu L-F, Boldin MP, Chaudhry A, Lin L-L, Taganov KD, Hanada T, Yoshimura A, Baltimore D, Rudensky AY (2010) Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142:914–929. Scholar
  107. Lucas B, Bumann D, Walduck A, Koesling J, Develioglu L, Meyer TF, Aebischer T (2001) Adoptive transfer of CD4+ T cells specific for subunit A of Helicobacter pylori urease reduces H. pylori stomach colonization in mice in the absence of interleukin-4 (IL-4)/IL-13 receptor signaling. Infect Immun 69:1714–1721. Scholar
  108. Ma L, Chen Y, Zhang B, Liu G (2014) Increased microRNA-223 in Helicobacter pylori-associated gastric cancer contributed to cancer cell proliferation and migration. Biosci Biotechnol Biochem 78:602–608. Scholar
  109. Maeda S (2005) Nod2 mutation in Crohn’s disease potentiates NF- B activity and IL-1 processing. Science 307:734–738. Scholar
  110. Maeda S, Akanuma M, Mitsuno Y, Hirata Y, Ogura K, Yoshida H, Shiratori Y, Omata M (2001) Distinct mechanism of Helicobacter pylori mediated NF-kappa B activation between gastric cancer cells and monocytic cells. J Biol Chem 276:44856–44864. Scholar
  111. Maelfait J, Vercammen E, Janssens S, Schotte P, Haegman M, Magez S, Beyaert R (2008) Stimulation of Toll-like receptor 3 and 4 induces interleukin-1β maturation by caspase-8. J Exp Med 205:1967–1973. Scholar
  112. Man SM (2018) Inflammasomes in the gastrointestinal tract: infection, cancer and gut microbiota homeostasis. Nat Rev Gastroenterol Hepatol 15:721–737. Scholar
  113. Mandell L, Moran AP, Cocchiarella A, Houghton J, Taylor N, Fox JG, Wang TC, Kurt-Jones EA (2004) Intact gram-negative Helicobacter pylori, Helicobacter felis, and Helicobacter hepaticus bacteria activate innate immunity via toll-like receptor 2 but not toll-like receptor 4. Infect Immun 72:6446–6454.
  114. Mariathasan S, Monack DM (2007) Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 7:31–40. Scholar
  115. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440:228–232. Scholar
  116. Marotti B, Rocco A, De Colibus P, Compare D, de Nucci G, Staibano S, Tatangelo F, Romano M, Nardone G (2008) Interleukin-13 mucosal production in Helicobacter pylori-related gastric diseases. Dig Liver Dis 40:240–247. Scholar
  117. Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10:417–426CrossRefGoogle Scholar
  118. Matsumoto Y, Blanchard TG, Drakes ML, Basu M, Redline RW, Levine AD, Czinn SJ (2005) Eradication of Helicobacter pylori and resolution of gastritis in the gastric mucosa of IL-10-deficient mice. Helicobacter 10:407–415. Scholar
  119. Matsushima K, Isomoto H, Inoue N, Nakayama T, Hayashi T, Nakayama M, Nakao K, Hirayama T, Kohno S (2011) microRNA signatures in Helicobacter pylori-infected gastric mucosa. Int J Cancer 128:361–370. Scholar
  120. Mercier BC, Ventre E, Fogeron M-L, Debaud A-L, Tomkowiak M, Marvel J, Bonnefoy N (2012) NOD1 cooperates with TLR2 to enhance T cell receptor-mediated activation in CD8 T cells. PLoS ONE 7:e42170. Scholar
  121. Miao EA, Rajan JV, Aderem A (2011) Caspase-1-induced pyroptotic cell death: Caspase-1-induced pyroptotic cell death. Immunol Rev 243:206–214. Scholar
  122. Miao L, Liu K, Xie M, Xing Y, Xi T (2014) miR-375 inhibits Helicobacter pylori-induced gastric carcinogenesis by blocking JAK2-STAT3 signaling. Cancer Immunol Immunother 63:699–711. Scholar
  123. Miftahussurur M, Yamaoka Y (2015) Helicobacter pylori virulence genes and host genetic polymorphisms as risk factors for peptic ulcer disease. Expert Rev Gastroenterol Hepatol 9:1535–1547. Scholar
  124. Mogensen TH (2009) Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 22:240–273. Scholar
  125. Moran AP, Lindner B, Walsh EJ (1997) Structural characterization of the lipid A component of Helicobacter pylori rough- and smooth-form lipopolysaccharides. J Bacteriol 179:6453–6463CrossRefGoogle Scholar
  126. Morey P, Pfannkuch L, Pang E, Boccellato F, Sigal M, Imai-Matsushima A, Dyer V, Koch M, Mollenkopf H-J, Schlaermann P, Meyer TF (2018) Helicobacter pylori depletes cholesterol in gastric glands to prevent interferon gamma signaling and escape the inflammatory response. Gastroenterology 154:1391–1404.e9. Scholar
  127. Munari F, Fassan M, Capitani N, Codolo G, Vila-Caballer M, Pizzi M, Rugge M, Della Bella C, Troilo A, D’Elios S, Baldari CT, D’Elios MM, de Bernard M (2014) Cytokine BAFF released by Helicobacter pylori-infected macrophages triggers the Th17 response in human chronic gastritis. J Immunol 193:5584–5594. Scholar
  128. Mustapha P, Paris I, Garcia M, Tran CT, Cremniter J, Garnier M, Faure J-P, Barthes T, Boneca IG, Morel F, Lecron J-C, Burucoa C, Bodet C (2014) Chemokines and antimicrobial peptides have a cag—dependent early response to Helicobacter pylori infection in primary human gastric epithelial cells. Infect Immun 82:2881–2889. Scholar
  129. Nagashima H, Iwatani S, Cruz M, Jiménez Abreu JA, Uchida T, Mahachai V, Vilaichone R-K, Graham DY, Yamaoka Y (2015) Toll-like receptor 10 in Helicobacter pylori infection. J Infect Dis 212:1666–1676. Scholar
  130. Naumann M, Sokolova O, Tegtmeyer N, Backert S (2017) Helicobacter pylori: a paradigm pathogen for subverting host cell signal transmission. Trends Microbiol 25(4):316–328.
  131. Ng GZ, Menheniott TR, Every AL, Stent A, Judd LM, Chionh YT, Dhar P, Komen JC, Giraud AS, Wang TC, McGuckin MA, Sutton P (2016) The MUC1 mucin protects against Helicobacter pylori pathogenesis in mice by regulation of the NLRP3 inflammasome. Gut 65:1087–1099. Scholar
  132. Nguyen TT, Kim S-J, Park JM, Hahm KB, Lee H-J (2015) Repressed TGF-β signaling through CagA-Smad3 interaction as pathogenic mechanisms of Helicobacter pylori-associated gastritis. J Clin Biochem Nutr 57:113–120. Scholar
  133. Noto JM, Piazuelo MB, Chaturvedi R, Bartel CA, Thatcher EJ, Delgado A, Romero-Gallo J, Wilson KT, Correa P, Patton JG, Peek RM (2013) Strain-specific suppression of microRNA-320 by carcinogenic Helicobacter pylori promotes expression of the antiapoptotic protein Mcl-1. Am J Physiol Gastrointest Liver Physiol 305:G786–G796. Scholar
  134. Obonyo M, Cole SP, Datta SK, Guiney DG (2006) Evidence for interleukin-1-independent stimulation of interleukin-12 and down-regulation by interleukin-10 in Helicobacter pylori-infected murine dendritic cells deficient in the interleukin-1 receptor. FEMS Immunol Med Microbiol 47:414–419. Scholar
  135. Odenbreit S, Linder S, Gebert-Vogl B, Rieder G, Moran AP, Haas R (2006) Interleukin-6 induction by Helicobacter pylori in human macrophages is dependent on phagocytosis. Helicobacter 11:196–207CrossRefGoogle Scholar
  136. Oertli M, Noben M, Engler DB, Semper RP, Reuter S, Maxeiner J, Gerhard M, Taube C, Müller A (2013) Helicobacter pylori γ-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance. Proc Natl Acad Sci USA 110:3047–3052. Scholar
  137. Ortega-Gómez A, Perretti M, Soehnlein O (2013) Resolution of inflammation: an integrated view. EMBO Mol Med 5(5):661–674. Scholar
  138. Pachathundikandi K, Backert S (2018a) Heptose 1,7-bisphosphate directed TIFA oligomerization: a novel PAMP-recognizing signaling platform in the control of bacterial infections. Gastroenterology 154:778–783. Scholar
  139. Pachathundikandi SK, Backert S (2016) Differential expression of interleukin 1β during Helicobacter pylori infection of Toll-like Receptor 2 (TLR2)- and TLR10-expressing HEK293 cell lines. J Infect Dis 214:166–167. Scholar
  140. Pachathundikandi SK, Backert S (2018b) Helicobacter pylori controls NLRP3 expression by regulating hsa-miR-223-3p and IL-10 in cultured and primary human immune cells. Innate Immun 24:11–23. Scholar
  141. Pachathundikandi SK, Brandt S, Madassery J, Backert S (2011) Induction of TLR-2 and TLR-5 expression by Helicobacter pylori switches cagPAI-dependent signalling leading to the secretion of IL-8 and TNF-α. PLoS ONE 6:e19614. Scholar
  142. Pachathundikandi SK, Lind J, Tegtmeyer N, El-Omar EM, Backert S (2015) Interplay of the gastric pathogen Helicobacter pylori with Toll-like receptors. Biomed Res Int 2015:192420. Scholar
  143. Pachathundikandi SK, Müller A, Backert S (2016) Inflammasome activation by Helicobacter pylori and its implications for persistence and immunity. Curr Top Microbiol Immunol 397:117–31. Scholar
  144. Pachathundikandi SK, Tegtmeyer N, Backert S (2013) Signal transduction of Helicobacter pylori during interaction with host cell protein receptors of epithelial and immune cells. Gut Microbes 4:454–474. Scholar
  145. Pagliari M, Munari F, Toffoletto M, Lonardi S, Chemello F, Codolo G, Millino C, Della Bella C, Pacchioni B, Vermi W, Fassan M, de Bernard M, Cagnin S (2017) Helicobacter pylori affects the antigen presentation activity of macrophages modulating the expression of the immune receptor CD300E through miR-4270. Front Immunol 8:1288. Scholar
  146. Panthel K, Faller G, Haas R (2003) Colonization of C57BL/6J and BALB/c wild-type and knockout mice with Helicobacter pylori: effect of vaccination and implications for innate and acquired immunity. Infect Immun 71:794–800CrossRefGoogle Scholar
  147. Pellicanò A, Sebkova L, Monteleone G, Guarnieri G, Imeneo M, Pallone F, Luzza F (2007) Interleukin-12 drives the Th1 signaling pathway in Helicobacter pylori-infected human gastric mucosa. Infect Immun 75:1738–1744. Scholar
  148. Peng L-S, Zhuang Y, Li W-H, Zhou Y-Y, Wang T-T, Chen N, Cheng P, Li B-S, Guo H, Yang S-M, Chen W-S, Zou Q-M (2014) Elevated interleukin-32 expression is associated with Helicobacter pylori-related gastritis. PLoS ONE 9:e88270. Scholar
  149. Pérez-Pérez GI, Shepherd VL, Morrow JD, Blaser MJ (1995) Activation of human THP-1 cells and rat bone marrow-derived macrophages by Helicobacter pylori lipopolysaccharide. Infect Immun 63:1183–1187PubMedPubMedCentralGoogle Scholar
  150. Piao J-Y, Lee HG, Kim S-J, Kim D-H, Han H-J, Ngo H-K-C, Park S-A, Woo J-H, Lee J-S, Na H-K, Cha Y-N, Surh Y-J (2016) Helicobacter pylori activates IL-6-STAT3 signaling in human gastric cancer cells: potential roles for reactive oxygen species. Helicobacter 21:405–416. Scholar
  151. Pinchuk IV, Morris KT, Nofchissey RA, Earley RB, Wu J-Y, Ma TY, Beswick EJ (2013) Stromal cells induce Th17 during Helicobacter pylori infection and in the gastric tumor microenvironment. PLoS ONE 8:e53798. Scholar
  152. Polk DB, Peek RM (2010) Helicobacter pylori: gastric cancer and beyond. Nat Rev Cancer 10:403–414. Scholar
  153. Posselt G, Backert S, Wessler S (2013) The functional interplay of Helicobacter pylori factors with gastric epithelial cells induces a multi-step process in pathogenesis. Cell Commun Signal 11:77. Scholar
  154. Quiding-Järbrink M, Raghavan S, Sundquist M (2010) Enhanced M1 macrophage polarization in human Helicobacter pylori associated atrophic gastritis and in vaccinated mice. PLoS ONE 5:e15018. Scholar
  155. Rad R, Ballhorn W, Voland P, Eisenächer K, Mages J, Rad L, Ferstl R, Lang R, Wagner H, Schmid RM, Bauer S, Prinz C, Kirschning CJ, Krug A (2009) Extracellular and intracellular pattern recognition receptors cooperate in the recognition of Helicobacter pylori. Gastroenterology 136:2247–2257. Scholar
  156. Rad R, Brenner L, Krug A, Voland P, Mages J, Lang R, Schwendy S, Reindl W, Dossumbekova A, Ballhorn W, Wagner H, Schmid RM, Bauer S, Prinz C (2007) Toll-like receptor-dependent activation of antigen-presenting cells affects adaptive immunity to Helicobacter pylori. Gastroenterology 133:150–163.e3. Scholar
  157. Rapsinski GJ, Wynosky-Dolfi MA, Oppong GO, Tursi SA, Wilson RP, Brodsky IE, Tükel Ç (2015) Toll-like receptor 2 and NLRP3 cooperate to recognize a functional bacterial amyloid, curli. Infect Immun 83:693–701. Scholar
  158. Rhee SH, Keates AC, Moyer MP, Pothoulakis C (2004) MEK is a key modulator for TLR5-induced interleukin-8 and MIP3alpha gene expression in non-transformed human colonic epithelial cells. J Biol Chem 279:25179–25188. Scholar
  159. Rizzuti D, Ang M, Sokollik C, Wu T, Abdullah M, Greenfield L, Fattouh R, Reardon C, Tang M, Diao J, Schindler C, Cattral M, Jones NL (2015) Helicobacter pylori inhibits dendritic cell maturation via interleukin-10-mediated activation of the signal transducer and activator of transcription 3 pathway. J Innate Immun 7:199–211. Scholar
  160. Romi B, Soldaini E, Pancotto L, Castellino F, Del Giudice G, Schiavetti F (2011) Helicobacter pylori induces activation of human peripheral γδ+ T lymphocytes. PLoS ONE 6:e19324. Scholar
  161. Rossi AFT, Cadamuro ACT, Biselli-Périco JM, Leite KRM, Severino FE, Reis PP, Cordeiro JA, Silva AE (2016) Interaction between inflammatory mediators and miRNAs in Helicobacter pylori infection. Cell Microbiol 18:1444–1458. Scholar
  162. Saito Y, Suzuki H, Tsugawa H, Suzuki S, Matsuzaki J, Hirata K, Hibi T (2011) Dysfunctional gastric emptying with down-regulation of muscle-specific microRNAs in Helicobacter pylori-infected mice. Gastroenterology 140:189–198. Scholar
  163. Sakitani K, Hirata Y, Hayakawa Y, Serizawa T, Nakata W, Takahashi R, Kinoshita H, Sakamoto K, Nakagawa H, Akanuma M, Yoshida H, Maeda S, Koike K (2012) Role of interleukin-32 in Helicobacter pylori-induced gastric inflammation. Infect Immun 80:3795–3803. Scholar
  164. Salama NR, Hartung ML, Müller A (2013) Life in the human stomach: persistence strategies of the bacterial pathogen Helicobacter pylori. Nat Rev Microbiol 11:385–399. Scholar
  165. Schmausser B, Josenhans C, Endrich S, Suerbaum S, Sitaru C, Andrulis M, Brändlein S, Rieckmann P, Müller-Hermelink HK, Eck M (2004) Downregulation of CXCR1 and CXCR2 expression on human neutrophils by Helicobacter pylori: a new pathomechanism in H. pylori infection? Infect Immun 72:6773–6779. Scholar
  166. Serhan CN (2017) Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms. FASEB J 31:1273–1288. Scholar
  167. Serrano C, Wright SW, Bimczok D, Shaffer CL, Cover TL, Venegas A, Salazar MG, Smythies LE, Harris PR, Smith PD (2013) Downregulated Th17 responses are associated with reduced gastritis in Helicobacter pylori-infected children. Mucosal Immunol 6:950–959. Scholar
  168. Shao L, Chen Z, Soutto M, Zhu S, Lu H, Romero-Gallo J, Peek R, Zhang S, El-Rifai W (2019) Helicobacter pylori-induced miR-135b-5p promotes cisplatin resistance in gastric cancer. FASEB J 33:264–274. Scholar
  169. Shi Y, Liu X-F, Zhuang Y, Zhang J-Y, Liu T, Yin Z, Wu C, Mao X-H, Jia K-R, Wang F-J, Guo H, Flavell RA, Zhao Z, Liu K-Y, Xiao B, Guo Y, Zhang W-J, Zhou W-Y, Guo G, Zou Q-M (2010) Helicobacter pylori-induced Th17 responses modulate Th1 cell responses, benefit bacterial growth, and contribute to pathology in mice. J Immunol 184:5121–5129. Scholar
  170. Shih S-C (2005) Expression patterns of transforming growth factor-beta and its receptors in gastric mucosa of patients with refractory gastric ulcer. World J Gastroenterol 11:136. Scholar
  171. Shimoyama T, Fukuda S, Liu Q, Nakaji S, Fukuda Y, Sugawara K (2002) Production of chemokines and reactive oxygen species by human neutrophils stimulated by Helicobacter pylori. Helicobacter 7:170–174CrossRefGoogle Scholar
  172. Shiotani A, Uedo N, Iishi H, Murao T, Kanzaki T, Kimura Y, Kamada T, Kusunoki H, Inoue K, Haruma K (2012) Helicobacter pylori eradication did not improve dysregulation of specific oncogenic miRNAs in intestinal metaplastic glands. J Gastroenterol 47:988–998. Scholar
  173. Sjökvist Ottsjö L, Flach C-F, Nilsson S, Malefyt R de W, Walduck AK, Raghavan S (2015) Defining the roles of IFN-γ and IL-17A in inflammation and protection against Helicobacter pylori infection. PLoS ONE 10:e0131444.
  174. Sjomina O, Pavlova J, Niv Y, Leja M (2018) Epidemiology of Helicobacter pylori infection. Helicobacter 23:e12514. Scholar
  175. Slomiany BL, Slomiany A (2017) Role of LPS-elicited signaling in triggering gastric mucosal inflammatory responses to Helicobacter pylori: modulatory effect of ghrelin. Inflammopharmacology 25:415–429. Scholar
  176. Smith KD, Andersen-Nissen E, Hayashi F, Strobe K, Bergman MA, Barrett SL, Cookson BT, Aderem A (2003a) Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility. Nat Immunol 4:1247–1253. Scholar
  177. Smith MF, Mitchell A, Li G, Ding S, Fitzmaurice AM, Ryan K, Crowe S, Goldberg JB (2003b) Toll-like receptor (TLR) 2 and TLR5, but not TLR4, are required for Helicobacter pylori-induced NF-kappa B activation and chemokine expression by epithelial cells. J Biol Chem 278:32552–32560. Scholar
  178. Sommer F, Faller G, Röllinghoff M, Kirchner T, Mak TW, Lohoff M (2001) Lack of gastritis and of an adaptive immune response in interferon regulatory factor-1-deficient mice infected with Helicobacter pylori. Eur J Immunol 31:396–402.;2-yCrossRefPubMedGoogle Scholar
  179. Song M, Su H, Zhang L, Ma J, Li J, Pan K, You W (2013) Genetic polymorphisms of miR-146a and miR-27a, Helicobacter pylori infection, and risk of gastric lesions in a Chinese population. PLoS ONE 8:e61250. Scholar
  180. Stead CM, Beasley A, Cotter RJ, Trent MS (2008) Deciphering the unusual acylation pattern of Helicobacter pylori lipid A. J Bacteriol 190:7012–7021. Scholar
  181. Su B, Ceponis PJM, Lebel S, Huynh H, Sherman PM (2003) Helicobacter pylori activates Toll-like receptor 4 expression in gastrointestinal epithelial cells. Infect Immun 71:3496–3502CrossRefGoogle Scholar
  182. Sugimoto M, Ohno T, Graham DY, Yamaoka Y (2011) Helicobacter pylori outer membrane proteins on gastric mucosal interleukin 6 and 11 expression in Mongolian gerbils: OMPs of H. pylori and gerbils. J Gastroenterol Hepatol 26:1677–1684. Scholar
  183. Sugimoto MA, Sousa LP, Pinho V, Perretti M, Teixeira MM (2016) Resolution of inflammation: what controls its onset? Front Immunol 7:160. Scholar
  184. Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820. Scholar
  185. Tang B, Li N, Gu J, Zhuang Y, Li Q, Wang HG, Fang Y, Yu B, Zhang JY, Xie QH,Chen L, Jiang XJ, Xiao B, Zou QM, Mao XH (2012) Compromised autophagy by MIR30B benefits the intracellular survival of Helicobacter pylori. Autophagy 8:1045–1057.
  186. Teng G, Dai Y, Chu Y, Li J, Zhang H, Wu T, Shuai X, Wang W (2018) Helicobacter pylori induces caudal-type homeobox protein 2 and cyclooxygenase 2 expression by modulating microRNAs in esophageal epithelial cells. Cancer Sci 109:297–307. Scholar
  187. Torok AM, Bouton AH, Goldberg JB (2005) Helicobacter pylori induces interleukin-8 secretion by Toll-like receptor 2- and Toll-like receptor 5-dependent and -independent pathways. Infect Immun 73:1523–1531. Scholar
  188. Tran AX, Whittimore JD, Wyrick PB, McGrath SC, Cotter RJ, Trent MS (2006) The lipid A 1-phosphatase of Helicobacter pylori is required for resistance to the antimicrobial peptide polymyxin. J Bacteriol 188:4531–4541. Scholar
  189. Travassos LH, Carneiro LAM, Ramjeet M, Hussey S, Kim Y-G, Magalhães JG, Yuan L, Soares F, Chea E, Le Bourhis L, Boneca IG, Allaoui A, Jones NL, Nuñez G, Girardin SE, Philpott DJ (2010) Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol 11:55–62. Scholar
  190. Tsai C-C, Kuo T-Y, Hong Z-W, Yeh Y-C, Shih K-S, Du S-Y, Fu H-W (2015) Helicobacter pylori neutrophil-activating protein induces release of histamine and interleukin-6 through G protein-mediated MAPKs and PI3 K/Akt pathways in HMC-1 cells. Virulence 6:755–765. Scholar
  191. Varga MG, Shaffer CL, Sierra JC, Suarez G, Piazuelo MB, Whitaker ME, Romero-Gallo J, Krishna US, Delgado A, Gomez MA, Good JAD, Almqvist F, Skaar EP, Correa P, Wilson KT, Hadjifrangiskou M, Peek RM (2016) Pathogenic Helicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system. Oncogene 35:6262–6269.
  192. Wang F, Liu J, Zou Y, Jiao Y, Huang Y, Fan L, Li X, Yu H, He C, Wei W, Wang H, Sun G (2017) MicroRNA-143-3p, up-regulated in Helicobacter pylori-positive gastric cancer, suppresses tumor growth, migration and invasion by directly targeting AKT2. Oncotarget 8:28711–28724.
  193. Wang Y-C, Chen C-L, Sheu B-S, Yang Y-J, Tseng P-C, Hsieh C-Y, Lin C-F (2014) Helicobacter pylori infection activates Src homology-2 domain-containing phosphatase 2 to suppress IFN-γ signaling. J Immunol 193:4149–4158. Scholar
  194. White JR, Winter JA, Robinson K (2015) Differential inflammatory response to Helicobacter pylori infection: etiology and clinical outcomes. J Inflamm Res 8:137–147. Scholar
  195. Wightman B, Ha I, Ruvkun G (1993) Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75:855–862CrossRefGoogle Scholar
  196. Wilson KT, Crabtree JE (2007) Immunology of Helicobacter pylori: insights into the failure of the immune response and perspectives on vaccine studies. Gastroenterology 133:288–308. Scholar
  197. Wu K, Yang L, Li C, Zhu C-H, Wang X, Yao Y, Jia Y-J (2014) MicroRNA-146a enhances Helicobacter pylori induced cell apoptosis in human gastric cancer epithelial cells. Asian Pac J Cancer Prev 15:5583–5586CrossRefGoogle Scholar
  198. Wu MS, Lee CW, Shun CT, Wang HP, Lee WJ, Sheu JC, Lin JT (1998) Clinicopathological significance of altered loci of replication error and microsatellite instability-associated mutations in gastric cancer. Cancer Res 58:1494–1497PubMedGoogle Scholar
  199. Wu K, Zhu C, Yao Y, Wang X, Song J, Zhai J (2016) MicroRNA-155-enhanced autophagy in human gastric epithelial cell in response to Helicobacter pylori. Saudi J Gastroenterol 22:30–36. Scholar
  200. Xiao B, Liu Z, Li B-S, Tang B, Li W, Guo G, Shi Y, Wang F, Wu Y, Tong W-D, Guo H, Mao X-H, Zou Q-M (2009) Induction of microRNA-155 during Helicobacter pylori infection and its negative regulatory role in the inflammatory response. J Infect Dis 200:916–925. Scholar
  201. Xie G, Li W, Li R, Wu K, Zhao E, Zhang Y, Zhang P, Shi L, Wang D, Yin Y, Deng R, Tao K (2017) Helicobacter pylori promote B7-H1 expression by suppressing miR-152 and miR-200b in gastric cancer cells. PLoS ONE 12:e0168822. Scholar
  202. Yamaoka Y, Kita M, Kodama T, Sawai N, Tanahashi T, Kashima K, Imanishi J (1998) Chemokines in the gastric mucosa in Helicobacter pylori infection. Gut 42:609–617CrossRefGoogle Scholar
  203. Yang X-J, Si R-H, Liang Y-H, Ma B-Q, Jiang Z-B, Wang B, Gao P (2016) Mir-30d increases intracellular survival of Helicobacter pylori through inhibition of autophagy pathway. World J Gastroenterol 22:3978–3991. Scholar
  204. Ye F, Tang C, Shi W, Qian J, Xiao S, Gu M, Dang Y, Liu J, Chen Y, Shi R, Zhang G (2015) A MDM2-dependent positive-feedback loop is involved in inhibition of miR-375 and miR-106b induced by Helicobacter pylori lipopolysaccharide. Int J Cancer 136:2120–2131. Scholar
  205. Yokota S, Ohnishi T, Muroi M, Tanamoto K, Fujii N, Amano K (2007) Highly-purified Helicobacter pylori LPS preparations induce weak inflammatory reactions and utilize Toll-like receptor 2 complex but not Toll-like receptor 4 complex. FEMS Immunol Med Microbiol 51:140–148. Scholar
  206. Yun CH, Lundgren A, Azem J, Sjöling A, Holmgren J, Svennerholm A-M, Lundin BS (2005) Natural killer cells and Helicobacter pylori infection: bacterial antigens and interleukin-12 act synergistically to induce gamma interferon production. Infect Immun 73:1482–1490. Scholar
  207. Zhang XS, Tegtmeyer N, Traube L, Jindal S, Perez-Perez G, Sticht H, Backert S, Blaser MJ (2015) A specific A/T polymorphism in Western tyrosine phosphorylation B-motifs regulates Helicobacter pylori CagA epithelial cell interaction. PloS Pathog 11:1004621. Scholar
  208. Zhang YM, Noto JM, Hammond CE, Barth JL, Argraves WS, Backert S, Peek RM Jr,Smolka AJ (2014) Helicobacter pylori-induced posttranscriptional regulation of H-K-ATPase α-subunit gene expression by miRNA. Am J Physiol Gastrointest Liver Physiol 306:G606-613.
  209. Zhang Z, Li Z, Gao C, Chen P, Chen J, Liu W, Xiao S, Lu H (2008) miR-21 plays a pivotal role in gastric cancer pathogenesis and progression. Lab Invest 88:1358–1366. Scholar
  210. Zhao Y, Yokota K, Ayada K, Yamamoto Y, Okada T, Shen L, Oguma K (2007) Helicobacter pylori heat-shock protein 60 induces interleukin-8 via a Toll-like receptor (TLR)2 and mitogen-activated protein (MAP) kinase pathway in human monocytes. J Med Microbiol 56:154–164. Scholar
  211. Zhou X, Li L, Su J, Zhang G (2014a) Decreased miR-204 in Helicobacter pylori-associated gastric cancer promotes cancer cell proliferation and invasion by targeting SOX4. PLoS ONE 9:e101457. Scholar
  212. Zhou X, Li X, Wu M (2018) miRNAs reshape immunity and inflammatory responses in bacterial infection. Signal Transduct Target Ther 3:14. Scholar
  213. Zhou X, Xu G, Yin C, Jin W, Zhang G (2014b) Down-regulation of miR-203 induced by Helicobacter pylori infection promotes the proliferation and invasion of gastric cancer by targeting CASK. Oncotarget 5:11631–11640.
  214. Zhu Y, Jiang Q, Lou X, Ji X, Wen Z, Wu J, Tao H, Jiang T, He W, Wang C, Du Q, Zheng S, Mao J, Huang J (2012) microRNAs up-regulated by CagA of Helicobacter pylori induce intestinal metaplasia of gastric epithelial cells. PLoS ONE 7:e35147. Scholar
  215. Zhuang Y, Cheng P, Liu X, Peng L, Li B, Wang T, Chen N, Li W, Shi Y, Chen W, Pang KC, Zeng M, Mao X, Yang S, Guo H, Guo G, Liu T, Zuo Q, Yang H, Yang L, Mao F, Lv Y, Zou Q (2015) A pro-inflammatory role for Th22 cells in Helicobacter pylori-associated gastritis. Gut 64:1368–1378. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Suneesh Kumar Pachathundikandi
    • 1
  • Nicole Blaser
    • 1
  • Steffen Backert
    • 1
    Email author
  1. 1.Department of BiologyDivision of Microbiology, Friedrich Alexander University Erlangen-NurembergErlangenGermany

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