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Cyclophilin A is a new M cell marker of bovine intestinal epithelium

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Abstract

Microfold (M) cells in the follicle-associated epithelium (FAE) of Peyer’s patches contribute to the mucosal immune response by the transcytosis of microorganisms. The mechanism by which M cells take up microorganisms, and the functional proteins by which they do this, are not clear. In order to explore one such protein, we developed a 2H5-F3 monoclonal antibody (2H5-F3 mAb) through its binding to bovine M cells, and identified the antibody reactive molecule as cyclophilin A (Cyp-A). The localization patterns of Cyp-A were very similar to the localization pattern of cytokeratin (CK) 18-positive M cells. Cyp-A was identified at the luminal surface of CK18-positive M cells in bovine jejunal and ileal FAE. The membranous localization of Cyp-A in the bovine intestinal cell line (BIE cells) increased as cells differentiated toward M cells, as determined by flow cytometry analysis. Additionally, BIE cells released Cyp-A to the extracellular space and the differentiation of BIE cells to M cells increased the secretion of Cyp-A, as determined by western blotting. Accordingly, Cyp-A may be localized in M cells in the small intestinal epithelium of cattle. The rise of the membranous localization and secretion of Cyp-A by differentiation toward M cells indicates that Cyp-A has an important role in the function of M cells. While Cyp-A of the M cell membrane may contribute to the uptake of viruses with peptidyl-prolyl cis-trans isomerase activity, in the extracellular space Cyp-A may work as a chemokine and contribute to the distribution of immuno-competent cells.

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References

  • Andres PG, Beck PL, Mizoguchi E, Mizoguchi A, Bhan AK, Dawson T, Kuziel WA, Maeda N, MacDermott RP, Podolsky DK, Reinecker HC (2000) Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sodium sulfate-mediated colitis: lack of CC chemokine receptor 5 expression results in a NK1.1 + lymphocyte-associated Th2-type immune response in the intestine. J Immunol 164:6303–12

    Article  CAS  PubMed  Google Scholar 

  • Banks C, Bateman A, Payne R, Johnson P, Sheron N (2003) Chemokine expression in IBD. Mucosal Chemokine expression is unselectively increased in both ulcerative colitis and Crohn’s disease. J Pathol 199:28–35

    Article  PubMed  Google Scholar 

  • Beyaz F, Asti RN (2004) Development of ileal Peyer’s patches and follicle associated epithelium in bovine fetuses. Anat Histol Embryol 33:172–179

    Article  CAS  PubMed  Google Scholar 

  • Bjarnason I, MacPherson A, Hollander D (1995) Intestinal permeability: an overview. Gastroenterology 108:1566–1581

    Article  CAS  PubMed  Google Scholar 

  • Bjerknes M, Cheng H (2005) Gastrointestinal stem cells. II. Intestinal stem cells. Am J Physiol Gastrointest Liver Physiol 289:G381–G387

    Article  CAS  PubMed  Google Scholar 

  • Bockman DE (1983) Functional histology of appendix. Arch Histol Jpn 46:271–292

    Article  CAS  PubMed  Google Scholar 

  • Brittan M, Wright NA (2004) Stem cell in gastrointestinal structure and neoplastic development. Gut 53:899–910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bye WA, Allan CH, Trier JS (1984) Structure, distribution, and origin of M cells in Peyer’s patches of mouse ileum. Gastroenterology 86:789–801

    CAS  PubMed  Google Scholar 

  • Clark MA, Jepson MA, Simmons NL, Booth TA, Hirst BH (1993) Differential expression of lectin-binding sites defines mouse intestinal M-cells. J Histochem Cytochem 41:1679–1687

    Article  CAS  PubMed  Google Scholar 

  • Clark MA, Hirst BH, Jepson MA (1998) M-cell surface beta1 integrin expression and invasion-mediated targeting of Yersinia pseudotuberculosis to mouse Peyer’s patch M cells. Infect Immun 66:1237–1243

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fischer G, Wittmann-Liebold B, Lang K, Kiefhaber T, Schmid FX (1989) Cyclophilin and Peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature 337:476–8

    Article  CAS  PubMed  Google Scholar 

  • Flanagan WM, Corthésy B, Bram RJ, Crabtree GR (1991) Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature 352:803–807

    Article  CAS  PubMed  Google Scholar 

  • Fotopoulos G, Harari A, Michetti P, Trono D, Pantaleo G, Kraehenbuhl JP (2002) Transepithelial transport of HIV-1 by M cells is receptor-mediated. Proc Natl Acad Sci U S A 99:9410–9414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fruman DA, Burakoff SJ, Bierer BE (1994) Immunophilins in protein folding and immunosuppression. FASEB J 8:391–400

    CAS  PubMed  Google Scholar 

  • Gebert A (1997) The role of M cells in the protection of mucosal membranes. Histochem Cell Biol 108:455–470

    Article  CAS  PubMed  Google Scholar 

  • Gebert A, Rothkötter HJ, Pabst R (1994) Cytokeratin 18 is an M-cell marker in porcine Peyer’s patches. Cell Tissue Res 276:213–221

    Article  CAS  PubMed  Google Scholar 

  • Giannasca PJ, Giannasca KT, Falk P, Gordon JI, Neutra MR (1994) Regional differences in glycoconjugates of intestinal M cells in mice: potential targets for mucosal vaccines. Am J Physiol Gastrointest Liver Physiol 267:G1108–G1121

    CAS  Google Scholar 

  • Gullberg E, Söderholm JD (2006) Peyer’s patches and M cells as potential sites of the inflammatory onset in Crohn’s disease. Ann N Y Acad Sci 1072:218–32

    Article  CAS  PubMed  Google Scholar 

  • Handschumacher RE, Harding MW, Rice J, Drugge RJ, Speicher DW (1984) Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science 226:544–547

    Article  CAS  PubMed  Google Scholar 

  • Hase K, Murakami T, Takatsu H, Shimaoka T, Iimura M, Hamura K, Kawano K, Ohshima S, Chihara R, Itoh K, Yonehara S, Ohno H (2006) The membrane-bound chemokine CXCL16 expressed on follicle-associated epithelium and M cells mediates lympho-epithelial interaction in GALT. J Immunol 176:43–51

    Article  CAS  PubMed  Google Scholar 

  • Hase K, Kawano K, Nochi T, Pontes GS, Fukuda S, Ebisawa M, Kadokura K, Tobe T, Fujimura Y, Kawano S, Yabashi A, Waguri S, Nakato G, Kimura S, Murakami T, Iimura M, Hamura K, Fukuoka S, Lowe AW, Itoh K, Kiyono H, Ohno H (2009) Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response. Nature 462:226–30

    Article  CAS  PubMed  Google Scholar 

  • Heggebø R, Press CM, Gunnes G, Lie KI, Tranulis MA, Ulvund M, Groschup MH, Landsverk T (2000) Distribution of prion protein in the ileal Peyer’s patch of scrapie-free lambs and lambs naturally and experimentally exposed to the scrapie agent. J Gen Virol 81:2327–37

    Article  PubMed  Google Scholar 

  • Heppner FL, Christ AD, Klein MA, Prinz M, Fried M, Kraehenbuhl JP, Aguzzi A (2001) Transepithelial prion transport by M cells. Nat Med 7:976–7

    Article  CAS  PubMed  Google Scholar 

  • Hondo T, Kanaya T, Takakura I, Watanabe H, Takahashi Y, Nagasawa Y, Terada S, Ohwada S, Watanabe K, Kitazawa H, Rose MT, Yamaguchi T, Aso H (2011) Cytokeratin 18 is a specific marker of bovine intestinal M cell. Am J Physiol Gastrointest Liver Physiol 300:442–53

    Article  Google Scholar 

  • Jepson MA, Mason CM, Bennett MK, Simmons NL, Hirst BH (1992) Co-expression of vimentin and cytokeratins in M cells of rabbit intestinal lymphoid follicle-associated epithelium. Histochem J 24:33–39

    Article  CAS  PubMed  Google Scholar 

  • Kanaya T, Miyazawa K, Takakura I, Itani W, Watanabe K, Ohwada S, Kitazawa H, Rose MT, McConochie HR, Okano H, Yamaguchi T, Aso H (2008) Differentiation of a murine intestinal epithelial cell line (MIE) toward the M cell lineage. Am J Physiol Gastrointest Liver Physiol 295:273–84

    Article  Google Scholar 

  • Kernéis S, Bogdanova A, Kraehenbuhl JP, Pringault E (1997) Conversion by Peyer’s patch lymphocytes of human enterocytes into M cells that transport bacteria. Science 277:949–52

    Article  PubMed  Google Scholar 

  • Kraehenbuhl JP, Neutra MR (2000) Epithelial M cells: differentiation and function. Annu Rev Cell Dev Biol 16:301–332

    Article  CAS  PubMed  Google Scholar 

  • Kucharzik T, Lügering A, Lügering N, Rautenberg K, Linnepe M, Cichon C, Reichelt R, Stoll R, Schmidt MA, Domschke W (2000) Characterization of M cell development during indomethacin-induced ileitis in rats. Aliment Pharmacol Ther 14:247–256

    Article  CAS  PubMed  Google Scholar 

  • Landsverk T (1979) The gastrointestinal mucosa in young milk-fed calves. A scanning electron and light microscopic investigation. Acta Vet Scand 20:572–582

    CAS  PubMed  Google Scholar 

  • Landsverk T (1981a) Peyer’s patches and the follicle-associated epithelium in diarrheic calves. Pathomorphology, morphometry and acid phosphatase histochemistry. Acta Vet Scand 122:459–471

    Google Scholar 

  • Landsverk T (1981b) The epithelium covering Peyer’s patches in young milk-fed celves. An ultrastructural and enzyme histochemical investigation. Acta Vet Scand 22:198–210

    CAS  PubMed  Google Scholar 

  • Landsverk T (1984) Is the ileo-caecal Peyer’s patch in ruminants a mammalian “bursa-equivalent”? Acta Pathol Microbiol Immunol Scand A 92:77–79

    CAS  PubMed  Google Scholar 

  • Landsverk T (1987) The follicle-associated epithelium of ileal Peyer’s patch in ruminants is distinguished by its shedding of 50 nm particles. Immunol Cell Biol 65:251–261

    Article  PubMed  Google Scholar 

  • Landsverk T (1988) Phagocytosis and transcytosis by the follicle-associated epithelium of the ileal Peyer’s patch in calves. Immunol Cell Biol 66:261–268

    Article  PubMed  Google Scholar 

  • MacDermott RP (1999) Chemokines in the inflammatory bowel diseases. J Clin Immunol 19:266–72

    Article  CAS  PubMed  Google Scholar 

  • Madara JL, Nash S, Moore R, Atisook K (1990) Structure and function of the intestinal epithelial barrier in health and disease. Monogr Pathol 31:306–24

    PubMed  Google Scholar 

  • Marshman E, Booth C, Potten CS (2002) The intestinal epithelial stem cell. BioEssays 24:91–98

    Article  PubMed  Google Scholar 

  • Miyazawa K, Aso H, Honda M, Kido T, Minashima T, Kanaya T, Watanabe K, Ohwada S, Rose MT, Yamaguchi T (2006) Identification of bovine dendritic cell phenotype from bovine peripheral blood. Res Vet Sci 81:40–45

    Article  CAS  PubMed  Google Scholar 

  • Miyazawa K, Hondo T, Kanaya T, Tanaka S, Takakura I, Itani W, Rose MT, Kitazawa H, Yamaguchi T, Aso H (2010a) Characterization of newly established bovine intestinal epithelial cell line. Histochem Cell Biol 133:125–34

    Article  CAS  PubMed  Google Scholar 

  • Miyazawa K, Kanaya T, Takakura I, Tanaka S, Hondo T, Watanabe H, Rose MT, Kitazawa H, Yamaguchi T, Katamine S, Nishida N, Aso H (2010b) Transcytosis of murine-adapted bovine spongiform encephalopathy agents in an in vitro bovine M cell model. J Virol 84:12285–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Momotani E, Whipple DL, Thiermann AB, Cheville NF (1988) Role of M cells and macrophages in the entrance of Mycobacterium paratuberculosis into dome of ileal Peyer’s patches in calves. Vet Pathol 25:131–137

    Article  CAS  PubMed  Google Scholar 

  • Neutra MR (1999) M cells in antigen sampling in mucosal tissues. Curr Top Microbiol Immunol 236:17–32

    CAS  PubMed  Google Scholar 

  • Neutra MR, Pringault E, Kraehenbuhl JP (1996) Antigen sampling across epithelial barriers and induction of mucosal immune responses. Annu Rev Immunol 14:275–300

    Article  CAS  PubMed  Google Scholar 

  • Owen RL, Jones AL (1974) Epithelial cell specialization within human Peyer’s patches: an ultrastructural study of intestinal lymphoid follicles. Gastroenterology 66:189–203

    CAS  PubMed  Google Scholar 

  • Paar M, Liebler EM, Pohlenz JF (1992) Uptake of ferritin by follicle-associ- ated epithelium in the colon of calves. Vet Pathol 29:120–128

    Article  CAS  PubMed  Google Scholar 

  • Parsons KR, Bland AP, Hall GA (1991) Follicle associated epithelium of the gut associated lymphoid tissue of cattle. Vet Pathol 28:22–29

    Article  CAS  PubMed  Google Scholar 

  • Rautenberg K, Cichon C, Heyer G, Demel M, Schmidt MA (1996) Immunocytochemical characterization of the follicle-associated epithelium of Peyer’s patches: anti-cytokeratin 8 antibody (clone 4.1.18) as a molecular marker for rat M cells. Eur J Cell Biol 71:363–370

    CAS  PubMed  Google Scholar 

  • Regoli M, Bertelli E, Borghesi C, Nicoletti C (1995) Three-dimensional (3D-) reconstruction of M cells in rabbit Peyer’s patches; definition of the intraepithelial compartment of the follicle-associated epithelium. Anat Rec 243:19–26

    Article  CAS  PubMed  Google Scholar 

  • Reynolds JD, Morris B (1983) The evolution and involution of Peyer’s patches in fetal and postnatal sheep. Eur J Immunol 13:627–635

    Article  CAS  PubMed  Google Scholar 

  • Sharma R, Schumacher U, Adam E (1998) Lectin histochemistry reveals the appearance of M-cells in Peyer’s patches of SCID mice after syngeneic normal bone marrow transplantation. J Histochem Cytochem 46:143–148

    Article  CAS  PubMed  Google Scholar 

  • Sherry B, Yarlett N, Strupp A, Cerami A (1992) Identification of cyclophilin as a proinflammatory secretory product of lipopolysaccharide-activated macrophages. Proc Natl Acad Sci U S A 89:3511–5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song F, Zhang X, Ren XB, Zhu P, Xu J, Wang L, Li YF, Zhong N, Ru Q, Zhang DW, Jiang JL, Xia B, Chen ZN (2011) Cyclophilin A (CyPA) induces chemotaxis independent of its peptidylprolyl cis-trans isomerase activity: direct binding between CyPA and the ectodomain of CD147. J Biol Chem 286:8197–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suzuki J, Jin ZG, Meoli DF, Matoba T, Berk BC (2006) Cyclophilin A is secreted by a vesicular pathway in vascular smooth muscle cells. Circ Res 98:811–7

    Article  CAS  PubMed  Google Scholar 

  • Takakura I, Miyazawa K, Kanaya T, Itani W, Watanabe K, Ohwada S, Watanabe H, Hondo T, Rose MT, Mori T, Sakaguchi S, Nishida N, Katamine S, Yamaguchi T, Aso H (2011) Orally administered prion protein is incorporated by m cells and spreads into lymphoid tissues with macrophages in prion protein knockout mice. Am J Pathol 179(3):1301–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Torres-Medina A (1981) Morphologic characteristics of the epithelial surface of aggregated lymphoid follicles (Peyer’s patches) in the small intestine of newborn gnotobiotic calves and pigs. Am J Vet Res 42:232–236

    CAS  PubMed  Google Scholar 

  • Towers GJ, Hatziioannou T, Cowan S, Goff SP, Luban J, Bieniasz PD (2003) Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors. Nat Med 9:1138–43

    Article  CAS  PubMed  Google Scholar 

  • Turner JR (2006) Molecular basis of epithelial barrier regulation: from basic mechanisms to clinical application. Am J Pathol 169:1901–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang P, Heitman J (2005) The cyclophilins. Genome Biol 6:226

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhao X, Sato A, Dela Cruz CS, Linehan M, Luegering A, Kucharzik T, Shirakawa AK, Marquez G, Farber JM, Williams I, Iwasaki A (2003) CCL9 is secreted by the follicle-associated epithelium and recruits dome region Peyer’s patch CD11b + dendritic cells. J Immunol 171:2797–803

    Article  CAS  PubMed  Google Scholar 

  • Zhou D, Mei Q, Li J, He H (2012) Cyclophilin A and viral infections. Biochem Biophys Res Commun 424:647–50

    Article  CAS  PubMed  Google Scholar 

  • Zhu P, Ding J, Zhou J, Dong WJ, Fan CM, Chen ZN (2005) Expression of CD147 on monocytes/macrophages in rheumatoid arthritis: its potential role in monocyte accumulation and matrix metalloproteinase production. Arthritis Res 7:1023–1033

    Article  Google Scholar 

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Author contributions

T.H., S.S. and H.A. conception and design of research; T.H., S.S., Y.N., S.T., H.W., X.C., K.W., S.O. and H.A. performed experiments; T.H. and S.S. analyzed data; T.H., S.S., K.W., S.O., H.K., T.N. and H.A. interpreted results of experiments; T.H. and S.S. prepared figures; T.H., S.S., and S.T. drafted manuscript; T.H., S.S., M.T.R. and H.A. edited and revised the manuscript; H.A. approved final version of manuscript.

Grants

This study was supported by a Grant-in-Aid for Scientific Research (B) (no. 15H04586) and a Grant-in-Aid for Exploratory Research (no. 26660217) from the Japan Society for the Promotion of Science (JSPS).

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    Authors and Affiliations

    1. Cellar Biology Laboratory, Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori Amamiyamachi, Aoba-ku, 981-8555, Sendai, Japan

      Tetsuya Hondo, Shunsuke Someya, Yuya Nagasawa, Shunsuke Terada, Hitoshi Watanabe, Xiangning Chen, Kouichi Watanabe, Shyuichi Ohwada, Tomonori Nochi & Hisashi Aso

    2. Department of Physiology and Metabolism, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Japan

      Hitoshi Watanabe

    3. Food Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan

      Haruki Kitazawa

    4. Institute of Biological, Environmental and Rural Sciences, Aberystwyth University, Cardiganshire, UK

      Michael T. Rose

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    1. Tetsuya Hondo
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    2. Shunsuke Someya
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    Correspondence to Hisashi Aso.

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    Tetsuya Hondo, Shunsuke Someya and Yuya Nagasawa contributed equally to this work.

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    Hondo, T., Someya, S., Nagasawa, Y. et al. Cyclophilin A is a new M cell marker of bovine intestinal epithelium. Cell Tissue Res 364, 585–597 (2016). https://doi.org/10.1007/s00441-015-2342-1

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