Ovalbumin-Derived Peptides Activate Retinoic Acid Signalling Pathways and Induce Regulatory Responses Through Toll-Like Receptor Interactions
Abstract
:1. Introduction
2. Materials and Methods
2.1. Proteins, Hydrolysates, and Animals
2.2. Dendritic Cell Cultures
2.3. Co-Cultures of Dendritic Cells and T Cells
2.4. T Cell Cultures
2.5. Gene Expression Analyses
2.6. Flow Cytometry Analyses
2.7. Statistical Analyses
3. Results
3.1. Dendritic Cells Pulsed with the Hydrolysate of Ovalbumin with PepsinAcquire Tolerogenic Properties
3.2. IL-4 Enhances the Effects of the Hydrolysate of Ovalbumin with Pepsin on Aldh1a2 Expression in Bone Marrow-Dendritic Cells
3.3. The Hydrolysate of Ovalbumin with Pepsin does not Promote CD103 Expression on Bone Marrow-dendritic Cells
3.4. The Hydrolysate of Ovalbumin with Pepsin Enhances Aldh1a2 and Il10 Expression, and ALDH Activity in Dendritic Cells by Interacting with Toll-like Receptors
3.5. The Hydrolysate of Ovalbumin with Pepsin Conditions Dendritic Cells to Induce a Regulatory Phenotype in CD4+ T cells, but also Promotes the Development of Regulatory T Cells without the Intermediation of Antigen Presenting Cells
4. Discussion
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
References
- Mucida, D.; Kutchukhidze, N.; Erazo, A.; Russo, M.; Lafaille, J.J.; Curotto de Lafaille, M.A. Oral tolerance in the absence of naturally occurring Tregs. J. Clin. Investig. 2005, 115, 1923–1933. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Coombes, J.L.; Siddiqui, K.R.; Arancibia-Cárcamo, C.V.; Hall, J.; Sun, C.M.; Belkaid, Y.; Powrie, F. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J. Exp. Med. 2007, 204, 1757–1764. [Google Scholar] [CrossRef] [PubMed]
- Cassani, B.; Villablanca, E.J.; De Calisto, J.; Wang, S.; Mora, J.R. Vitamin A and immune regulation: Role of retinoic acid in gut-associated dendritic cell education, immune protectionand tolerance. Mol. Aspects Med. 2012, 33, 63–76. [Google Scholar] [CrossRef] [Green Version]
- Saurer, L.; McCullough, K.C.; Summerfield, A. In vitro induction of mucosa-type dendritic cells byall-trans retinoic acid. J. Immunol. 2007, 179, 3504–3514. [Google Scholar] [CrossRef] [Green Version]
- Yokota, A.; Takeuchi, H.; Maeda, N.; Ohoka, Y.; Kato, C.; Song, S.Y.; Iwata, M. GM-CSF and IL-4 synergistically trigger dendritic cells to acquire retinoic acid-producing capacity. Int. Immunol. 2009, 21, 361–377. [Google Scholar] [CrossRef] [Green Version]
- Villablanca, E.J.; Wang, S.; de Calisto, J.; Gomes, D.C.; Kane, M.A.; Napoli, J.L.; Blaner, W.S.; Kagechika, H.; Blomhoff, R.; Rosemblatt, M.; et al. MyD88 and retinoic acid signaling pathways interact to modulate gastrointestinal activities of dendritic cells. Gastroenterology 2011, 141, 176–185. [Google Scholar] [CrossRef] [Green Version]
- Mora, J.R.; Iwata, M.; Eksteen, B.; Song, S.Y.; Junt, T.; Senman, B.; Otipoby, K.L.; Yokota, A.; Takeuchi, H.; Ricciardi-Castagnoli, P.; et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 2006, 314, 1157–1160. [Google Scholar] [CrossRef] [Green Version]
- Sun, C.M.; Hall, J.A.; Blank, R.B.; Bouladoux, N.; Oukka, M.; Mora, J.R.; Belkaid, Y. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 2007, 204, 1775–1785. [Google Scholar] [CrossRef] [Green Version]
- Mucida, D.; Pino-Lagos, K.; Kim, G.; Nowak, E.; Benson, M.J.; Kronenberg, M.; Noelle, R.J.; Cheroutre, H. Retinoic acid can directly promote TGF-beta-mediated Foxp3+ Treg cell conversion of naive T cells. Immunity 2009, 30, 471–472. [Google Scholar] [CrossRef] [Green Version]
- Maynard, C.L.; Hatton, R.D.; Helms, W.S.; Oliver, J.R.; Stephensen, C.B.; Weaver, C.T. Contrasting roles for all-trans retinoic acid in TGF-β-mediated induction of Foxp3 and Il10 genes in developing regulatory T cells. J. Exp. Med. 2009, 206, 343–357. [Google Scholar] [CrossRef] [Green Version]
- Hill, J.A.; Hall, J.A.; Sun, C.M.; Cai, Q.; Ghyselinck, N.; Chambon, P.; Belkaid, Y.; Mathis, D.; Benoist, C. Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+ CD44hi cells. Immunity 2008, 29, 758–770. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lozano-Ojalvo, D.; Pérez-Rodríguez, L.; Pablos-Tanarro, A.; Molina, E.; López-Fandiño, R. Hydrolysed ovalbumin offers more effective preventive and therapeutic protection against egg allergy than the intact protein. Clin. Exp. Allergy 2017, 47, 1342–1354. [Google Scholar] [CrossRef] [PubMed]
- Lozano-Ojalvo, D.; Martínez-Blanco, M.; Pérez-Rodríguez, L.; Molina, E.; Peláez, C.; Requena, T.; López-Fandiño, R. Egg white peptide-based immunotherapy enhances vitamin A metabolism and induces RORγt+ regulatory T cells. J. Funct. Foods 2019, 52, 204–211. [Google Scholar] [CrossRef]
- Lochner, M.; Peduto, L.; Cherrier, M.; Sawa, S.; Langa, F.; Varona, R.; Riethmacher, D.; Si-Tahar, M.; Di Santo, J.P.; Eberl, G. In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORγt+ T cells. J. Exp. Med. 2008, 205, 1381–1393. [Google Scholar] [CrossRef]
- Ohnmacht, C.; Park, J.H.; Cording, S.; Wing, J.B.; Atarashi, K.; Obata, Y.; Gaboriau-Routhiau, V.; Marques, R.; Dulauroy, S.; Fedoseeva, M.; et al. The microbiota regulates type 2 immunity through RORγt+ T cells. Science 2015, 349, 989–993. [Google Scholar] [CrossRef]
- Roth-Walter, F.; Moskovskich, A.; Gómez-Casado, C.; Diaz-Perales, A.; Oida, K.; Singer, J.; Kinaciyan, T.; Fuchs, H.C.; Jensen-Jarolim, E. Immune suppressive effect of cinnamaldehyde due to inhibition of proliferation and induction of apoptosis in immune cells: Implications in cancer. PLoS ONE 2014, 9, e108402. [Google Scholar] [CrossRef]
- Lozano-Ojalvo, D.; Molina, E.; López-Fandiño, R. Hypoallergenic hydrolysates of egg white proteins modulate allergen-induced responses induced ex vivo on spleen cells from sensitized mice. Food Res. Int. 2016, 89, 661–669. [Google Scholar] [CrossRef]
- Lozano-Ojalvo, D.; Pérez-Rodríguez, L.; Pablos-Tanarro, A.; López-Fandiño, R.; Molina, E. Pepsin treatment of whey proteins under high pressure produces hypoallergenic hydrolysates. Innov. Food Sci. Emerg. Technol. 2017, 43, 154–162. [Google Scholar] [CrossRef]
- Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the the 2−ΔΔCT method. Methods 2001, 25, 402–408. [Google Scholar] [CrossRef]
- Vasanthakumar, A.; Kallies, A. IL-27 paves different roads to Tr1. Eur. J. Immunol. 2013, 43, 882–885. [Google Scholar] [CrossRef] [Green Version]
- Schiering, C.; Krausgruber, T.; Chomka, A.; Fröhlich, A.; Adelmann, K.; Wohlfert, E.A.; Pott, J.; Griseri, T.; Bollrath, J.; Hegazy, A.N.; et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 2014, 513, 564–568. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Amsen, D.; Helbig, C.; Backer, R.A. Notch in T cell differentiation: All things considered. Trends Immunol. 2015, 36, 802–814. [Google Scholar] [CrossRef] [PubMed]
- Gopisetty, A.; Bhattacharya, P.; Haddad, C.; Bruno, J.C., Jr.; Vasu, C.; Miele, L.; Prabhakar, B.S. OX40L/Jagged1 cosignaling by GM-CSF-induced bone marrow-derived dendritic cells is required for the expansion of functional regulatory T cells. J. Immunol. 2013, 109, 5516–5525. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhao, G.N.; Jiang, D.S.; Li, H. Interferon regulatory factors: At the crossroads of immunity, metabolism, and disease. Biochim. Biophys. Acta 2015, 1852, 365–378. [Google Scholar] [CrossRef] [Green Version]
- Manicassamy, S.; Ravindran, R.; Deng, J.; Oluoch, H.; Denning, T.L.; Kasturi, S.P.; Rosenthal, K.M.; Evavold, B.D.; Pulendran, B. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat. Med. 2009, 15, 401–409. [Google Scholar] [CrossRef]
- Feng, T.; Cong, Y.; Qin, H.; Benveniste, E.N.; Elson, C.O. Generation of mucosal dendritic cells from bone marrow reveals a critical role of retinoic acid. J. Immunol. 2010, 185, 5915–5925. [Google Scholar] [CrossRef]
- 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. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat. Immunol. 2008, 9, 769–776. [Google Scholar] [CrossRef]
- Elgueta, R.; Sepulveda, F.E.; Vilches, F.; Vargas, L.; Mora, J.R.; Bono, M.R.; Rosemblatt, M. Imprinting of CCR9 on CD4 T cells requires IL-4 signaling on mesenteric lymph node dendritic cells. J. Immunol. 2008, 108, 6501–6507. [Google Scholar] [CrossRef] [Green Version]
- Zhu, B.; Buttrick, T.; Bassil, R.; Zhu, C.; Olah, M.; Wu, C.; Xiao, S.; Orent, W.; Elyaman, W.; Khoury, S.J. IL-4 and retinoic acid synergistically induce regulatory dendritic cells expressing Aldh1a2. J. Immunol. 2013, 191, 3139–3151. [Google Scholar] [CrossRef]
- Blázquez, A.B.; Berin, M.C. Gastrointestinal dendritic cells promote Th2 skewing via OX40L. J. Immunol. 2008, 180, 4441–4450. [Google Scholar] [CrossRef]
- Williams, J.W.; Tjota, M.Y.; Clay, B.S.; Vander Lugt, B.; Bandukwala, H.S.; Hrusch, C.L.; Decker, D.C.; Blaine, K.M.; Fixsen, B.R.; Singh, H.; et al. Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation. Nat. Commun. 2013, 4, 2990. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- López-Bravo, M.; Minguito de la Escalera, M.; Domínguez, P.M.; González-Cintado, L.; del Fresno, C.; Martín, P.; Martínez del Hoyo, G.; Ardavín, C. IL-4 blocks TH1-polarizing/inflammatory cytokine gene expression during monocyte-derived dendritic cell differentiation through histone hypoacetylation. J. Allergy Clin. Immunol. 2013, 132, 1409–1419. [Google Scholar] [CrossRef] [PubMed]
- Owaki, T.; Asakawa, M.; Fukai, F.; Mizuguchi, J.; Yoshimoto, T. IL-27 Induces Th1 differentiation via p38 MAPK/T-bet- and intercellular adhesion molecule-1/LFA-1/ERK1/2-dependent pathways. J. Immunol. 2006, 177, 7579–7587. [Google Scholar] [CrossRef] [PubMed]
- Dearman, R.J.; Cumberbatch, M.; Maxwell, G.; Basketter, D.A.; Kimber, I. Toll-like receptor ligand activation of murine bone marrow-derived dendritic cells. Immunology 2009, 126, 475–484. [Google Scholar] [CrossRef]
- Wang, S.; Villablanca, E.J.; De Calisto, J.; Gomes, D.C.; Nguyen, D.D.; Mizoguchi, E.; Kagan, J.C.; Reinecker, H.C.; Hacohen, N.; Nagler, C.; et al. MyD88-dependent TLR1/2 signals educate dendritic cells with gut-specific imprinting properties. J. Immunol. 2011, 187, 141–150. [Google Scholar] [CrossRef] [Green Version]
- Kiewiet, M.B.G.; Dekkers, R.; Gros, M.; van Neerven, R.J.J.; Groeneveld, A.; de Vos, P.; Faas, M.M. Toll-like receptor mediated activation is possibly involved in immunoregulating properties of cow’s milk hydrolysates. PLoS ONE 2017, 12, e0178191. [Google Scholar] [CrossRef] [Green Version]
- Muzio, M.; Bosisio, D.; Polentarutti, N.; D’amico, G.; Stoppacciaro, A.; Mancinelli, R.; van’tVeer, C.; Penton-Rol, G.; Ruco, L.P.; Allavena, P.; et al. Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: Selective expression of TLR3 in dendritic cells. J. Immunol. 2000, 164, 5998–6004. [Google Scholar] [CrossRef] [Green Version]
- Guzzo, C.; Ayer, A.; Basta, S.; Banfield, B.W.; Gee, K. IL-27 enhances LPS-induced proinflammatory cytokine production via upregulation of TLR4 expression and signaling in human monocytes. J. Immunol. 2012, 188, 864–873. [Google Scholar] [CrossRef] [Green Version]
- Tan, J.; McKenzie, C.; Vuillermin, P.J.; Goverse, G.; Vinuesa, C.G.; Mebius, R.E.; Macia, L.; Mackay, C.R. Dietary fiber and bacterial SCFA enhance oral tolerance and protect against food allergy through diverse cellular pathways. Cell Rep. 2016, 15, 2809–2824. [Google Scholar] [CrossRef] [Green Version]
- Amsen, D.; Blander, J.M.; Lee, G.R.; Tanigaki, K.; Honjo, T.; Flavell, R.A. Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 2004, 117, 515–526. [Google Scholar] [CrossRef] [Green Version]
- Su, Z.; Lin, J.; Lu, F.; Zhang, X.; Zhang, L.; Gandhi, N.B.; de Paiva, C.S.; Pflugfelder, S.C.; Li, D.Q. Potential autocrine regulation of interleukin-33/ST2 signaling of dendritic cells in allergic inflammation. Mucosal Immunol. 2013, 6, 921–930. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gajardo, T.; Pérez, F.; Terraza, C.; Campos-Mora, M.; Noelle, R.J.; Pino-Lagos, K. IL-33 enhances retinoicacidsignalingon CD4+ T cells. Cytokine 2016, 85, 120–122. [Google Scholar] [CrossRef] [PubMed]
- Fujimoto, K.; Karuppuchamy, T.; Takemura, N.; Shimohigoshi, M.; Machida, T.; Haseda, Y.; Aoshi, T.; Ishii, K.J.; Akira, S.; Uematsu, S. A new subset of CD103+ CD8α+ dendritic cells in the small intestine expresses TLR3, TLR7, and TLR9 and induces Th1 response and CTL activity. J. Immunol. 2011, 186, 6287–6295. [Google Scholar] [CrossRef] [Green Version]
- Esterházy, D.; Loschko, J.; London, M.; Jove, V.; Oliveira, T.Y.; Mucida, D. Classical dendritic cells are required for dietary antigen-mediated induction of peripheral Treg cells and tolerance. Nat. Immunol. 2016, 17, 545–555. [Google Scholar] [CrossRef]
- Luda, K.M.; Joeris, T.; Persson, E.K.; Rivollier, A.; Demiri, M.; Sitnik, K.M.; Pool, L.; Holm, J.B.; Melo-Gonzalez, F.; Richter, L.; et al. IRF8 transcription-factor-dependent classical dendritic cells are essential for intestinal T cell homeostasis. Immunity 2016, 44, 860–874. [Google Scholar] [CrossRef] [Green Version]
- de Kivit, S.; Kostadinova, A.I.; Kerperien, J.; AyechuMuruzabal, V.; Morgan, M.E.; Knippels, L.M.J.; Kraneveld, A.D.; Garssen, J.; Willemsen, L.E.M. Galectin-9 produced by intestinal epithelial cells enhances aldehyde dehydrogenase activity in dendritic cells in a PI3K- and p38-dependent manner. J. InnateImmun. 2017, 9, 609–620. [Google Scholar] [CrossRef]
- Awasthi, A.; Carrier, Y.; Peron, J.P.; Bettelli, E.; Kamanaka, M.; Flavell, R.A.; Kuchroo, V.K.; Oukka, M.; Weiner, H.L. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat. Immunol. 2007, 8, 1380–1389. [Google Scholar] [CrossRef]
- Dawicki, W.; Li, C.; Town, J.; Zhang, X.; Gordon, J.R. Therapeutic reversal of food allergen sensitivity by mature retinoic acid-differentiated dendritic cell induction of LAG3+ CD49b− Foxp3− regulatory T cells. J. Allergy Clin. Immunol. 2017, 139, 1608–1620.e3. [Google Scholar] [CrossRef] [Green Version]
- Round, J.L.; Mazmanian, S.K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl. Acad. Sci. USA 2010, 107, 12204–12209. [Google Scholar] [CrossRef] [Green Version]
- Wang, S.; Charbonnier, L.M.; Noval Rivas, M.; Georgiev, P.; Li, N.; Gerber, G.; Bry, L.; Chatila, T.A. MyD88 adaptor-dependent microbial sensing by regulatory T cells promotes mucosal tolerance and enforces commensalism. Immunity 2015, 43, 289–303. [Google Scholar] [CrossRef] [Green Version]
- Crellin, N.K.; Garcia, R.V.; Hadisfar, O.; Allan, S.E.; Steiner, T.S.; Levings, M.K. Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+ CD25+ T regulatory cells. J. Immunol. 2005, 175, 8051–8059. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zanin-Zhorov, A.; Cahalon, L.; Tal, G.; Margalit, R.; Lider, O.; Cohen, I.R. Heat shock protein 60 enhances CD4+ CD25+ regulatory T cell function via innate TLR2 signaling. J. Clin. Invest. 2006, 116, 2022–2032. [Google Scholar] [CrossRef] [Green Version]
- Caramalho, I.; Lopes-Carvalho, T.; Ostler, D.; Zelenay, S.; Haury, M.; Demengeot, J. Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J. Exp. Med. 2003, 197, 403–411. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kanakry, C.G.; Ganguly, S.; Luznik, L. Situational aldehyde dehydrogenase expression by regulatory T cells may explain the contextual duality of cyclophosphamide as both a pro-inflammatory and tolerogenic agent. Oncoimmunology 2015, 4, e974393. [Google Scholar] [CrossRef] [Green Version]
- Chapoval, S.; Dasgupta, P.; Dorsey, N.J.; Keegan, A.D. Regulation of the T helper cell type 2 (Th2)/T regulatory cell (Treg) balance by IL-4 and STAT6. J. Leukoc. Biol. 2010, 87, 1011–1018. [Google Scholar] [CrossRef] [Green Version]
- Dardalhon, V.; Awasthi, A.; Kwon, H.; Galileos, G.; Gao, W.; Sobel, R.A.; Mitsdoerffer, M.; Strom, T.B.; Elyaman, W.; Ho, I.C.; et al. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3− effector T cells. Nat. Immunol. 2008, 9, 1347–1355. [Google Scholar] [CrossRef] [Green Version]
- Takaki, H.; Ichiyama, K.; Koga, K.; Chinen, T.; Takaesu, G.; Sugiyama, Y.; Kato, S.; Yoshimura, A.; Kobayashi, T. STAT6 inhibits TGF-beta1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor. J. Biol. Chem. 2008, 283, 14955–14962. [Google Scholar] [CrossRef] [Green Version]
- Rahman, A.H.; Taylor, D.K.; Turka, L.A. The contribution of direct TLR signaling to T cell responses. Immunol. Res. 2009, 45, 25–36. [Google Scholar] [CrossRef] [Green Version]
- Sefik, E.; Geva-Zatorsky, N.; Oh, S.; Konnikova, L.; Zemmour, D.; McGuire, A.M.; Burzyn, D.; Ortiz-Lopez, A.; Lobera, M.; Yang, J.; et al. Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells. Science 2015, 349, 993–997. [Google Scholar] [CrossRef] [Green Version]
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Martínez-Blanco, M.; Pérez-Rodríguez, L.; Lozano-Ojalvo, D.; Molina, E.; López-Fandiño, R. Ovalbumin-Derived Peptides Activate Retinoic Acid Signalling Pathways and Induce Regulatory Responses Through Toll-Like Receptor Interactions. Nutrients 2020, 12, 831. https://doi.org/10.3390/nu12030831
Martínez-Blanco M, Pérez-Rodríguez L, Lozano-Ojalvo D, Molina E, López-Fandiño R. Ovalbumin-Derived Peptides Activate Retinoic Acid Signalling Pathways and Induce Regulatory Responses Through Toll-Like Receptor Interactions. Nutrients. 2020; 12(3):831. https://doi.org/10.3390/nu12030831
Chicago/Turabian StyleMartínez-Blanco, Mónica, Leticia Pérez-Rodríguez, Daniel Lozano-Ojalvo, Elena Molina, and Rosina López-Fandiño. 2020. "Ovalbumin-Derived Peptides Activate Retinoic Acid Signalling Pathways and Induce Regulatory Responses Through Toll-Like Receptor Interactions" Nutrients 12, no. 3: 831. https://doi.org/10.3390/nu12030831