Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

Flagellin-Stimulated Production of Interferon-β Promotes Anti-Flagellin IgG2c and IgA Responses

  • Kang, Wondae (Division of Integrative Biosciences & Biotechnology, Pohang University of Science and Technology) ;
  • Park, Areum (Division of Integrative Biosciences & Biotechnology, Pohang University of Science and Technology) ;
  • Huh, Ji-Won (Division of Integrative Biosciences & Biotechnology, Pohang University of Science and Technology) ;
  • You, Gihoon (Division of Integrative Biosciences & Biotechnology, Pohang University of Science and Technology) ;
  • Jung, Da-Jung (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology) ;
  • Song, Manki (International Vaccine Institute) ;
  • Lee, Heung Kyu (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology) ;
  • Kim, You-Me (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology)
  • Received : 2019.11.28
  • Accepted : 2019.12.30
  • Published : 2020.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

Flagellin, a major structural protein of the flagellum found in all motile bacteria, activates the TLR5- or NLRC4 inflammasome-dependent signaling pathway to induce innate immune responses. Flagellin can also serve as a specific antigen for the adaptive immune system and stimulate anti-flagellin antibody responses. Failure to recognize commensal-derived flagellin in TLR5-deficient mice leads to the reduction in anti-flagellin IgA antibodies at steady state and causes microbial dysbiosis and mucosal barrier breach by flagellated bacteria to promote chronic intestinal inflammation. Despite the important role of anti-flagellin antibodies in maintaining the intestinal homeostasis, regulatory mechanisms underlying the flagellin-specific antibody responses are not well understood. In this study, we show that flagellin induces interferon-β (IFN-β) production and subsequently activates type I IFN receptor signaling in a TLR5- and MyD88-dependent manner in vitro and in vivo. Internalization of TLR5 from the plasma membrane to the acidic environment of endolysosomes was required for the production of IFN-β, but not for other pro-inflammatory cytokines. In addition, we found that anti-flagellin IgG2c and IgA responses were severely impaired in interferon-alpha receptor 1 (IFNAR1)-deficient mice, suggesting that IFN-β produced by the flagellin stimulation regulates anti-flagellin antibody class switching. Our findings shed a new light on the regulation of flagellin-mediated immune activation and may help find new strategies to promote the intestinal health and develop mucosal vaccines.

Keywords

References

  1. Adachi, O., Kawai, T., Takeda, K., Matsumoto, M., Tsutsui, H., Sakagami, M., Nakanishi, K., and Akira, S. (1998). Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9, 143-150. https://doi.org/10.1016/S1074-7613(00)80596-8
  2. Atif, S.M., Lee, S.J., Li, L.X., Uematsu, S., Akira, S., Gorjestani, S., Lin, X., Schweighoffer, E., Tybulewicz, V.L.J., and McSorley, S.J. (2015). Rapid CD4(+) T-cell responses to bacterial flagellin require dendritic cell expression of Syk and CARD9. Eur. J. Immunol. 45, 513-524. https://doi.org/10.1002/eji.201444744
  3. Aubry, C., Corr, S.C., Wienerroither, S., Goulard, C., Jones, R., Jamieson, A.M., Decker, T., O'Neill, L.A.J., Dussurget, O., and Cossart, P. (2012). Both TLR2 and TRIF contribute to interferon-beta production during Listeria infection. PLoS One 7, e33299. https://doi.org/10.1371/journal.pone.0033299
  4. Carvalho, F.A., Koren, O., Goodrich, J.K., Johansson, M.E., Nalbantoglu, I., Aitken, J.D., Su, Y., Chassaing, B., Walters, W.A., Gonzalez, A., et al. (2012). Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. Cell Host Microbe 12, 139-152. https://doi.org/10.1016/j.chom.2012.07.004
  5. Choi, Y.J., Im, E., Chung, H.K., Pothoulakis, C., and Rhee, S.H. (2010). TRIF mediates toll-like receptor 5-induced signaling in intestinal epithelial cells. J. Biol. Chem. 285, 37570-37578. https://doi.org/10.1074/jbc.M110.158394
  6. Ciacci-Woolwine, F., Blomfield, I.C., Richardson, S.H., and Mizel, S.B. (1998). Salmonella flagellin induces tumor necrosis factor alpha in a human promonocytic cell line. Infect. Immun. 66, 1127-1134. https://doi.org/10.1128/IAI.66.3.1127-1134.1998
  7. Cullender, T.C., Chassaing, B., Janzon, A., Kumar, K., Muller, C.E., Werner, J.J., Angenent, L.T., Bell, M.E., Hay, A.G., Peterson, D.A., et al. (2013). Innate and adaptive immunity interact to quench microbiome flagellar motility in the gut. Cell Host Microbe 14, 571-581. https://doi.org/10.1016/j.chom.2013.10.009
  8. Doyle, S., Vaidya, S., O'Connell, R., Dadgostar, H., Dempsey, P., Wu, T., Rao, G., Sun, R., Haberland, M., Modlin, R., et al. (2002). IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 17, 251-263. https://doi.org/10.1016/S1074-7613(02)00390-4
  9. Eaves-Pyles, T., Bu, H.F., Tan, X.D., Cong, Y.Z., Patel, J., Davey, R.A., and Strasser, J.E. (2011). Luminal-applied flagellin is internalized by polarized intestinal epithelial cells and elicits immune responses via the TLR5 dependent mechanism. PLoS One 6, e24869. https://doi.org/10.1371/journal.pone.0024869
  10. Felix, G., Duran, J.D., Volko, S., and Boller, T. (1999). Plants have a sensitive perception system for the most conserved domain of bacterial flagellin. Plant J. 18, 265-276. https://doi.org/10.1046/j.1365-313X.1999.00265.x
  11. Fitzgerald, K.A., Rowe, D.C., Barnes, B.J., Caffrey, D.R., Visintin, A., Latz, E., Monks, B., Pitha, P.M., and Golenbock, D.T. (2003). LPS-TLR4 signaling to IRF-3/7 and NF-kappa B involves the toll adapters TRAM and TRIF. J. Exp. Med. 198, 1043-1055. https://doi.org/10.1084/jem.20031023
  12. Flores-Langarica, A., Marshall, J.L., Hitchcock, J., Cook, C., Jobanputra, J., Bobat, S., Ross, E.A., Coughlan, R.E., Henderson, I.R., Uematsu, S., et al. (2012). Systemic flagellin immunization stimulates mucosal CD103(+) dendritic cells and drives Foxp3(+) regulatory T cell and IgA responses in the mesenteric lymph node. J. Immunol. 189, 5745-5754. https://doi.org/10.4049/jimmunol.1202283
  13. Franchi, L., Amer, A., Body-Malapel, M., Kanneganti, T.D., Ozoren, N., Jagirdar, R., Inohara, N., Vandenabeele, P., Bertin, J., Coyle, A., et al. (2006). Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nat. Immunol. 7, 576-582. https://doi.org/10.1038/ni1346
  14. Gewirtz, A.T., Navas, T.A., Lyons, S., Godowski, P.J., and Madara, J.L. (2001). Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J. Immunol. 167, 1882-1885. https://doi.org/10.4049/jimmunol.167.4.1882
  15. Gomez-Gomez, L. and Boller, T. (2000). FLS2: an LRR receptor-like kinase involved in the perception of the bacterial elicitor flagellin in Arabidopsis. Mol. Cell 5, 1003-1011. https://doi.org/10.1016/S1097-2765(00)80265-8
  16. Ha, H., Lee, J.H., Kim, H.N., Kwak, H.B., Kim, H.M., Lee, S.E., Rhee, J.H., Kim, H.H., and Lee, Z.H. (2008). Stimulation by TLR5 modulates osteoclast differentiation through STAT1/IFN-beta. J. Immunol. 180, 1382-1389. https://doi.org/10.4049/jimmunol.180.3.1382
  17. Hacker, H., Mischak, H., Miethke, T., Liptay, S., Schmid, R., Sparwasser, T., Heeg, K., Lipford, G.B., and Wagner, H. (1998). CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. EMBO J. 17, 6230-6240. https://doi.org/10.1093/emboj/17.21.6230
  18. Hajam, I.A., Dar, P.A., Shahnawaz, I., Jaume, J.C., and Lee, J.H. (2017). Bacterial flagellin-a potent immunomodulatory agent. Exp. Mol. Med. 49, e373. https://doi.org/10.1038/emm.2017.172
  19. Halff, E.F., Diebolder, C.A., Versteeg, M., Schouten, A., Brondijk, T.H., and Huizinga, E.G. (2012). Formation and structure of a NAIP5-NLRC4 inflammasome induced by direct interactions with conserved N- and C-terminal regions of flagellin. J. Biol. Chem. 287, 38460-38472. https://doi.org/10.1074/jbc.M112.393512
  20. Hayashi, F., Smith, K.D., Ozinsky, A., Hawn, T.R., Yi, E.C., Goodlett, D.R., Eng, J.K., Akira, S., Underhill, D.M., and Aderem, A. (2001). The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410, 1099-1103. https://doi.org/10.1038/35074106
  21. Hemont, C., Neel, A., Heslan, M., Braudeau, C., and Josien, R. (2013). Human blood mDC subsets exhibit distinct TLR repertoire and responsiveness. J. Leukoc. Biol. 93, 599-609. https://doi.org/10.1189/jlb.0912452
  22. Honda, K., Yanai, H., Mizutani, T., Negishi, H., Shimada, N., Suzuki, N., Ohba, Y., Takaoka, A., Yeh, W.C., and Taniguchi, T. (2004). Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc. Natl. Acad. Sci. U. S. A. 101, 15416-15421. https://doi.org/10.1073/pnas.0406933101
  23. Hoshino, K., Takeuchi, O., Kawai, T., Sanjo, H., Ogawa, T., Takeda, Y., Takeda, K., and Akira, S. (1999). Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol. 162, 3749-3752.
  24. Hu, Z., Zhou, Q., Zhang, C., Fan, S., Cheng, W., Zhao, Y., Shao, F., Wang, H.W., Sui, S.F., and Chai, J. (2015). Structural and biochemical basis for induced self-propagation of NLRC4. Science 350, 399-404. https://doi.org/10.1126/science.aac5489
  25. Huh, J.W., Shibata, T., Hwang, M., Kwon, E.H., Jang, M.S., Fukui, R., Kanno, A., Jung, D.J., Jang, M.H., Miyake, K., et al. (2014). UNC93B1 is essential for the plasma membrane localization and signaling of Toll-like receptor 5. Proc. Natl. Acad. Sci. U. S. A. 111, 7072-7077. https://doi.org/10.1073/pnas.1322838111
  26. Jang, M.H., Sougawa, N., Tanaka, T., Hirata, T., Hiroi, T., Tohya, K., Guo, Z., Umemoto, E., Ebisuno, Y., Yang, B.G., et al. (2006). CCR7 is critically important for migration of dendritic cells in intestinal lamina propria to mesenteric lymph nodes. J. Immunol. 176, 803-810. https://doi.org/10.4049/jimmunol.176.2.803
  27. Kagan, J.C., Su, T., Horng, T., Chow, A., Akira, S., and Medzhitov, R. (2008). TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta. Nat. Immunol. 9, 361-368. https://doi.org/10.1038/ni1569
  28. Kawai, T., Sato, S., Ishii, K.J., Coban, C., Hemmi, H., Yamamoto, M., Terai, K., Matsuda, M., Inoue, J., Uematsu, S., et al. (2004). Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat. Immunol. 5, 1061-1068. https://doi.org/10.1038/ni1118
  29. Kim, J., Huh, J., Hwang, M., Kwon, E.H., Jung, D.J., Brinkmann, M.M., Jang, M.H., Ploegh, H.L., and Kim, Y.M. (2013). Acidic amino acid residues in the juxtamembrane region of the nucleotide-sensing TLRs are important for UNC93B1 binding and signaling. J. Immunol. 190, 5287-5295. https://doi.org/10.4049/jimmunol.1202767
  30. Kofoed, E.M. and Vance, R.E. (2011). Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 477, 592-595. https://doi.org/10.1038/nature10394
  31. Langer, J.A. and Pestka, S. (1988). Interferon receptors. Immunol. Today 9, 393-400. https://doi.org/10.1016/0167-5699(88)91241-8
  32. Letran, S.E., Lee, S.J., Atif, S.M., Uematsu, S., Akira, S., and McSorley, S.J. (2011). TLR5 functions as an endocytic receptor to enhance flagellin-specific adaptive immunity. Eur. J. Immunol. 41, 29-38. https://doi.org/10.1002/eji.201040717
  33. Lopez-Yglesias, A.H., Zhao, X., Quarles, E.K., Lai, M.A., VandenBos, T., Strong, R.K., and Smith, K.D. (2014). Flagellin induces antibody responses through a TLR5-and inflammasome-independent pathway. J. Immunol. 192, 1587-1596. https://doi.org/10.4049/jimmunol.1301893
  34. Lowy, J. and McDonough, M.W. (1964). Structure of filaments produced by re-aggregation of Salmonella flagellin. Nature 204, 125-127. https://doi.org/10.1038/204125a0
  35. Lund, J., Sato, A., Akira, S., Medzhitov, R., and Iwasaki, A. (2003). Toll-like receptor 9-mediated recognition of herpes simplex virus-2 by plasmacytoid dendritic cells. J. Exp. Med. 198, 513-520. https://doi.org/10.1084/jem.20030162
  36. Marie, I., Durbin, J.E., and Levy, D.E. (1998). Differential viral induction of distinct interferon-alpha genes by positive feedback through interferon regulatory factor-7. EMBO J. 17, 6660-6669. https://doi.org/10.1093/emboj/17.22.6660
  37. McSorley, S.J., Ehst, B.D., Yu, Y., and Gewirtz, A.T. (2002). Bacterial flagellin is an effective adjuvant for CD4+ T cells in vivo. J. Immunol. 169, 3914-3919. https://doi.org/10.4049/jimmunol.169.7.3914
  38. Means, T.K., Hayashi, F., Smith, K.D., Aderem, A., and Luster, A.D. (2003). The toll-like receptor 5 stimulus bacterial flagellin induces maturation and chemokine production in human dendritic cells. J. Immunol. 170, 5165-5175. https://doi.org/10.4049/jimmunol.170.10.5165
  39. Miao, E.A., Alpuche-Aranda, C.M., Dors, M., Clark, A.E., Bader, M.W., Miller, S.I., and Aderem, A. (2006). Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat. Immunol. 7, 569-575. https://doi.org/10.1038/ni1344
  40. Muller, U., Steinhoff, U., Reis, L.F., Hemmi, S., Pavlovic, J., Zinkernagel, R.M., and Aguet, M. (1994). Functional role of type I and type II interferons in antiviral defense. Science 264, 1918-1921. https://doi.org/10.1126/science.8009221
  41. Odendall, C., Voak, A.A., and Kagan, J.C. (2017). Type III IFNs are commonly induced by bacteria-sensing TLRs and reinforce epithelial barriers during infection. J. Immunol. 199, 3270-3279. https://doi.org/10.4049/jimmunol.1700250
  42. Oh, J.Z., Ravindran, R., Chassaing, B., Carvalho, F.A., Maddur, M.S., Bower, M., Hakimpour, P., Gill, K.P., Nakaya, H.I., Yarovinsky, F., et al. (2014). TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination. Immunity 41, 478-492. https://doi.org/10.1016/j.immuni.2014.08.009
  43. Parlato, S., Santini, S.M., Lapenta, C., Di Pucchio, T., Logozzi, M., Spada, M., Glammarioli, A.M., Malorni, W., Fais, S., and Belardelli, F. (2001). Expression of CCR-7, MIP-3 beta, and Th-1 chemokines in type IIFN-induced monocyte-derived dendritic cells: importance for the rapid acquisition of potent migratory and functional activities. Blood 98, 3022-3029. https://doi.org/10.1182/blood.V98.10.3022
  44. Sanders, C.J., Yu, Y., Moore, D.A., 3rd, Williams, I.R., and Gewirtz, A.T. (2006). Humoral immune response to flagellin requires T cells and activation of innate immunity. J. Immunol. 177, 2810-2818. https://doi.org/10.4049/jimmunol.177.5.2810
  45. Sato, M., Hata, N., Asagiri, M., Nakaya, T., Taniguchi, T., and Tanaka, N. (1998). Positive feedback regulation of type I IFN genes by the IFN-inducible transcription factor IRF-7. FEBS Lett. 441, 106-110. https://doi.org/10.1016/S0014-5793(98)01514-2
  46. Scheu, S., Dresing, P., and Locksley, R.M. (2008). Visualization of IFNbeta production by plasmacytoid versus conventional dendritic cells under specific stimulation conditions in vivo. Proc. Natl. Acad. Sci. U. S. A. 105, 20416-20421. https://doi.org/10.1073/pnas.0808537105
  47. Shibata, T., Takemura, N., Motoi, Y., Goto, Y., Karuppuchamy, T., Izawa, K., Li, X., Akashi-Takamura, S., Tanimura, N., Kunisawa, J., et al. (2012). PRAT4A-dependent expression of cell surface TLR5 on neutrophils, classical monocytes and dendritic cells. Int. Immunol. 24, 613-623. https://doi.org/10.1093/intimm/dxs068
  48. Swanson, C.L., Wilson, T.J., Strauch, P., Colonna, M., Pelanda, R., and Torres, R.M. (2010). Type I IFN enhances follicular B cell contribution to the T cell-independent antibody response. J. Exp. Med. 207, 1485-1500. https://doi.org/10.1084/jem.20092695
  49. Takaoka, A., Yanai, H., Kondo, S., Duncan, G., Negishi, H., Mizutani, T., Kano, S., Honda, K., Ohba, Y., Mak, T.W., et al. (2005). Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434, 243-249. https://doi.org/10.1038/nature03308
  50. Thompson, J.M., Whitmore, A.C., Staats, H.F., and Johnston, R. (2008). The contribution of type I interferon signaling to immunity induced by alphavirus replicon vaccines. Vaccine 26, 4998-5003. https://doi.org/10.1016/j.vaccine.2008.07.011
  51. Uematsu, S., Fujimoto, K., Jang, M.H., Yang, B.G., Jung, Y.J., Nishiyama, M., Sato, S., Tsujimura, T., Yamamoto, M., Yokota, Y., et al. (2008). Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat. Immunol. 9, 769-776. https://doi.org/10.1038/ni.1622
  52. Uematsu, S., Jang, M.H., Chevrier, N., Guo, Z.J., Kumagai, Y., Yamamoto, M., Kato, H., Sougawa, N., Matsui, H., Kuwata, H., et al. (2006). Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c(+) lamina propria cells. Nat. Immunol. 7, 868-874. https://doi.org/10.1038/ni1362
  53. Vijay-Kumar, M., Aitken, J.D., and Gewirtz, A.T. (2008). Toll like receptor-5: protecting the gut from enteric microbes. Semin. Immunopathol. 30, 11-21. https://doi.org/10.1007/s00281-007-0100-5
  54. Yamamoto, M., Sato, S., Hemmi, H., Hoshino, K., Kaisho, T., Sanjo, H., Takeuchi, O., Sugiyama, M., Okabe, M., Takeda, K., et al. (2003). Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301, 640-643. https://doi.org/10.1126/science.1087262
  55. Yoon, S.I., Kurnasov, O., Natarajan, V., Hong, M., Gudkov, A.V., Osterman, A.L., and Wilson, I.A. (2012). Structural basis of TLR5-flagellin recognition and signaling. Science 335, 859-864. https://doi.org/10.1126/science.1215584
  56. Zanoni, I., Ostuni, R., Marek, L.R., Barresi, S., Barbalat, R., Barton, G.M., Granucci, F., and Kagan, J.C. (2011). CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Cell 147, 868-880. https://doi.org/10.1016/j.cell.2011.09.051
  57. Zhang, L., Chen, S., Ruan, J., Wu, J., Tong, A.B., Yin, Q., Li, Y., David, L., Lu, A., Wang, W.L., et al. (2015). Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization. Science 350, 404-409. https://doi.org/10.1126/science.aac5789
  58. Zhao, Y., Yang, J., Shi, J., Gong, Y.N., Lu, Q., Xu, H., Liu, L., and Shao, F. (2011). The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477, 596-600. https://doi.org/10.1038/nature10510

Cited by

  1. Harnessing innate immunity to eliminate SARS-CoV-2 and ameliorate COVID-19 disease vol.52, pp.5, 2020, https://doi.org/10.1152/physiolgenomics.00033.2020