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Evaluation of CHI3L-1 and CHIT-1 Expression in Differentiated and Polarized Macrophages

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Abstract

Chitinase 3-like protein 1 (CHI3L-1) and chitotriosidase (CHIT-1) are members of the chitinase family. CHI3L-1 is a newly recognized protein that is secreted by activated macrophages and neutrophils and expressed in a broad spectrum of inflammatory conditions and cancers. In human plasma, CHIT-1 activity has been proposed as a biochemical marker of macrophage activation. Although CHI3L-1 expression in inflammation is under examination, little is known regarding its regulation during macrophages’ full maturation and polarization. In this study, we compared CHI3L-1 and CHIT-1 modulation during monocyte to macrophage transition and polarization. Gene expression analysis was investigated by real-time PCR. We found that during the maturation of monocytes into macrophages, the expression of both CHI3L-1 and CHIT-1 increased exponentially over time. Additionally, we observed a different regulation of CHI3L-1 and CHIT-1 in undifferentiated monocytes under stimulation with lipopolysaccharide, interferon-γ, and interleukin-4, at the same concentration used to polarize macrophages. Our finding suggests that in the immune response, the role of CHI3L-1 and CHIT-1 is not restricted to innate immunity, but they are also protagonists in acquired immunity.

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References

  1. Johansen, J.S., N.A. Schultz, and B.V. Jensen. 2009. Plasma YKL-40: A potential new cancer biomarker? Future Oncology 5: 1065–1082.

    Article  PubMed  CAS  Google Scholar 

  2. Volck, B., P.A. Price, J.S. Johansen, O. Sorensen, T.L. Benfield, H.J. Nielsen, J. Calafat, and N. Borregarrd. 1998. YKL-40, a mammalian member of the chitinase family, is a matrix protein of specific granules in human neutrophils. Proceedings of the Association of American Physicians 110: 351–360.

    PubMed  CAS  Google Scholar 

  3. Rehli, M., H.H. Niller, C. Ammon, S. Langmann, L. Schwarzfischer, R. Andreesen, and S.W. Krause. 2003. Transcriptional regulation of CHI3L-1, a marker gene for late stages of macrophage differentiation. Journal of Biological Chemistry 278: 44058–44067.

    Article  PubMed  CAS  Google Scholar 

  4. Johansen, J.S., H.S. Jensen, and P.A. Price. 1993. A new biochemical marker for joint injury. Analysis of YKL-40 in serum and synovial fluid. British Journal of Rheumatology 32: 949–955.

    Article  PubMed  CAS  Google Scholar 

  5. Malinda, K.M., L. Ponce, H.K. Kleinman, L.M. Shackelton, and A.J. Millis. 1999. Gp38k, a protein synthesized by vascular smooth muscle cells, stimulates directional migration of human umbilical vein endothelial cells. Experimental Cell Research 250: 168–173.

    Article  PubMed  CAS  Google Scholar 

  6. Mizoguchi, E. 2006. Chitinase 3-like-1 exacerbates intestinal inflammation by enhancing bacterial adhesion and invasion in colonic epithelial cells. Gastroenterology 130: 398–411.

    Article  PubMed  CAS  Google Scholar 

  7. Johansen, J.S., M. Stoltenberg, M. Hansen, A. Florescu, K. Hørslev-Petersen, I. Lorenzen, and P.A. Price. 1999. Serum YKL-40 concentrations in patients with rheumatoid arthritis: Relation to disease activity. Rheumatology (Oxford, England) 38: 618–626.

    Article  CAS  Google Scholar 

  8. Specjalski, K., and E. Jassem. 2011. YKL-40 protein is a marker of asthma. The Journal of Asthma 48: 767–772.

    Article  PubMed  CAS  Google Scholar 

  9. Coffman, F.D. 2008. Chitinase 3-like-1 (CHI3L1): A putative disease marker at the interface of proteomics and glycomics. Critical Reviews in Clinical Laboratory Sciences 45: 531–562.

    Article  PubMed  CAS  Google Scholar 

  10. Johansen, J.S., P.E. Hoyer, L.A. Larsen, P.A. Price, and K. Mollgard. 2007. YKL-40 protein expression in the early developing human musculoskeletal system. Journal of Histochemistry and Cytochemistry 55: 1213–1228.

    Article  PubMed  CAS  Google Scholar 

  11. Johansen, J.S. 2006. Studies on serum YKL-40 as a biomarker in diseases with inflammation, tissue remodelling, fibroses and cancer. Danish Medical Bulletin 53: 172–209.

    PubMed  CAS  Google Scholar 

  12. Francescone, R.A., S. Scully, M. Faibish, S.L. Taylor, D. Oh, L. Moral, W. Yan, B. Bentley, and R. Shao. 2011. Role of YKL-40 in the angiogenesis, radioresistance, and progression of glioblastoma. Journal of Biological Chemistry 286: 15332–15343.

    Article  PubMed  CAS  Google Scholar 

  13. Johansen, J.S., S.E. Bojesen, A.K. Mylin, R. Frikke-Schmidt, P.A. Price, and B.G. Nordestgaard. 2009. Elevated plasma YKL-40 predicts increased risk of gastrointestinal cancer and decreased survival after any cancer diagnosis in the general population. Journal of Clinical Oncology 27: 572–578.

    Article  PubMed  Google Scholar 

  14. Kzhyshkowska, J., S. Mamidi, A. Gratchev, E. Kremmer, C. Schmuttermaier, L. Krusell, G. Haus, J. Utikal, K. Schledzewski, J. Scholtze, and S. Goerdt. 2006. Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway. Blood 107: 3221–3228.

    Article  PubMed  CAS  Google Scholar 

  15. Nielsen, A.R., P. Plomgaard, K.S. Krabbe, J.S. Johansen, and B.K. Pedersen. 2011. IL-6, but not TNF-α, increases plasma YKL-40 in human subjects. Cytokine 55: 152–155.

    Article  PubMed  CAS  Google Scholar 

  16. Boot, R.G., G.H. Renkema, A. Strijland, A.J. van Zonneveld, and J.M. Aerts. 1995. Cloning of a cDNA encoding chitotriosidase, a human chitinase produced by macrophages. Journal of Biological Chemistry 270: 26252–26256.

    Article  PubMed  CAS  Google Scholar 

  17. Bussink, A.P., M. van Eijk, G.H. Renkema, J.M. Aerts, and R.G. Boot. 2006. The biology of the Gaucher cell: The cradle of human chitinases. International Review of Cytology 252: 71–128.

    Article  PubMed  CAS  Google Scholar 

  18. Brinkman, J., F.A. Wijburg, C.E. Hollak, J.E. Groener, M. Verhoek, S. Scheij, J. Aten, R.G. Boot, and J.M. Aerts. 2005. Plasma chitotriosidase and CCL18: Early biochemical surrogate markers in type B Niemann-Pick disease. Journal of Inherited Metabolic Disease 28: 13–20.

    Article  PubMed  CAS  Google Scholar 

  19. Barone, R., J. Simporé, L. Malaguarnera, S. Pignatelli, and S. Musumeci. Plasma chitotriosidase activity in acute Plasmodium falciparum malaria. Clinica Chimica Acta 331:79–85

  20. Bargagli, E., C. Maggiorelli, and P. Rottoli. 2008. Human chitotriosidase: A potential new marker of sarcoidosis severity. Respiration 76: 234–238.

    Article  PubMed  CAS  Google Scholar 

  21. Comabella, M., C. Domínguez, J. Rio, P. Martín-Gallán, A. Vilches, N. Vilarrasa, C. Espejo, and X. Montalban. 2009. Plasma chitotriosidase activity in multiple sclerosis. Clinical Immunology 131: 216–222.

    Article  PubMed  CAS  Google Scholar 

  22. Boot, R.G., T.A. van Achterberg, B.E. van Aken, G.H. Renkema, M.J. Jacobs, J.M. Aerts, and C.J. de Vries. 1999. Strong induction of members of the chitinase family of proteins in atherosclerosis: Chitotriosidase and human cartilage gp-39 expressed in lesion macrophages. Arteriosclerosis, Thrombosis, and Vascular Biology 19: 687–694.

    Article  PubMed  CAS  Google Scholar 

  23. Malaguarnera, L., J. Simporè, D.A. Prodi, A. Angius, A. Sassu, I. Persico, R. Barone, and S. Musumeci. 2003. 24-bp duplication in exon 10 of human chitotriosidase gene from the sub-Saharan to the Mediterranean area: Role of parasitic diseases and environmental conditions. Genes and Immunity 4: 570–574.

    Article  PubMed  CAS  Google Scholar 

  24. Artieda, M., A. Cenarro, A. Gañán, A. Lukic, E. Moreno, J. Puzo, M. Pocoví, and F. Civeira. 2007. Serum chitotriosidase activity, a marker of activated macrophages, predicts new cardiovascular events independently of C-reactive protein. Cardiology 108: 297–306.

    Article  PubMed  CAS  Google Scholar 

  25. Palasik, W., U. Fiszer, W. Lechowicz, B. Czartoryska, M. Krzesiewicz, and A. Lugowska. 2005. Assessment of relations between clinical outcome of ischemic stroke and activity of inflammatory processes in the acute phase based on examination of selected parameters. European Neurology 53: 188–193.

    Article  PubMed  CAS  Google Scholar 

  26. Di Rosa, M., N. Dell'Ombra, A.M. Zambito, M. Malaguarnera, F. Nicoletti, and L. Malaguarnera. 2006. Chitotriosidase and inflammatory mediator levels in Alzheimer’s disease and cerebrovascular dementia. European Journal of Neuroscience 23: 2648–2656.

    Article  PubMed  Google Scholar 

  27. Malaguarnera, L., M. Di Rosa, A.M. Zambito, N. dell'Ombra, F. Nicoletti, and M. Malaguarnera. 2006. Chitotriosidase gene expression in Kupffer cells from patients with non-alcoholic fatty liver disease. Gut 55: 1313–1320.

    Article  PubMed  CAS  Google Scholar 

  28. Kzhyshkowska, J., A. Gratchev, and S. Goerdt. 2007. Human chitinases and chitinase-like proteins as indicators for inflammation and cancer. Biomark Insights 2: 128–146.

    PubMed  Google Scholar 

  29. Ross, R., X.L. Ross, H. Ghadially, T. Lahr, J. Schwing, J. Knop, and A.B. Reske-Kunz. 1999. Mouse langerhans cells differentially express an activated T cell-attracting CC chemokine. Journal of Investigative Dermatology 113: 991–998.

    Article  PubMed  CAS  Google Scholar 

  30. Martinez, F.O., A. Sica, and A.M. Mantovani Locati. 2008. Macrophage activation and polarization. Frontiers in Bioscience 13: 453–461.

    Article  PubMed  CAS  Google Scholar 

  31. Di Rosa, M., A.M. Zambito, A.R. Marsullo, G. Li Volti, and L. Malaguarnera. 2009. Prolactin induces chitotriosidase expression in human macrophages through PTK, PI3-K, and MAPK pathways. Journal of Cellular Biochemistry 107: 881–881.

    Article  PubMed  Google Scholar 

  32. Fagone, P., M. Di Rosa, M. Palumbo, C. De Gregorio, F. Nicoletti, and L. Malaguarnera. 2012. Modulation of heat shock proteins during macrophage differentiation. Inflammation Research 61: 1131–1139.

    Article  PubMed  CAS  Google Scholar 

  33. Quandt, K., K. Frech, H. Karas, E. Wingender, and T. Werner. 1995. MatInd and MatInspector: New fast and versatile tools for detection of consensus matches in nucleotide sequence data. Nucleic Acids Research 23: 4878–4884.

    Article  PubMed  CAS  Google Scholar 

  34. Heinemeyer, T., X. Chen, H. Karas, A.E. Kel, O.V. Kel, I. Liebich, T. Meinhardt, I. Reuter, F. Schacherer, and E. Wingender. 1999. Expanding the TRANSFAC database towards an expert system of regulatory molecular mechanisms. Nucleic Acids Research 27: 318–322.

    Article  PubMed  CAS  Google Scholar 

  35. Klingenhoff, A., K. Frech, K. Quandt, and T. Werner. 1999. Functional promoter modules can be detected by formal models independent of overall nucleotide sequence similarity. Bioinformatics 15: 180–186.

    Article  PubMed  CAS  Google Scholar 

  36. Frech, K., J. Danescu-Mayer, and T. Werner. 1997. A novel method to develop highly specific models for regulatory units detects a new LTR in GenBank which contains a functional promoter. Journal of Molecular Biology 270: 674–687.

    Article  PubMed  CAS  Google Scholar 

  37. Malaguarnera, L., M. Musumeci, M. Di Rosa, A. Scuto, and S. Musumeci. 2005. Interferon-gamma, tumor necrosis factor-alpha, and lipopolysaccharide promote chitotriosidase gene expression in human macrophages. Journal of Clinical Laboratory Analysis 19: 128–132.

    Article  PubMed  CAS  Google Scholar 

  38. Cakır, G., S. Gumus, E. Ucar, H. Kaya, E. Tozkoparan, E.O. Akgul, B. Karaman, O. Deniz, I. Kurt, M. Ozkan, and H. Bilgic. 2012. Serum chitotriosidase activity in pulmonary tuberculosis: Response to treatment and correlations with clinical parameters. Annals of Laboratory Medicine 32: 184–189.

    Article  PubMed  Google Scholar 

  39. Iyer, A., M. van Eijk, E. Silva, M. Hatta, W. Faber, J.M. Aerts, and P.K. Das. 2009. Increased chitotriosidase activity in serum of leprosy patients: Association with bacillary leprosy. Clinical Immunology 131: 501–509.

    Article  PubMed  CAS  Google Scholar 

  40. Malaguarnera, L., M. Di Rosa, A.M. Zambito, N. dell'Ombra, R. Di Marco, and M. Malaguarnera. 2006. Potential role of chitotriosidase gene in nonalcoholic fatty liver disease evolution. American Journal of Gastroenterology 101: 2060–2069.

    Article  PubMed  CAS  Google Scholar 

  41. Malaguarnera, L., L.N. Ohazuruike, C. Tsianaka, T. Antic, M. Di Rosa, and M. Malaguarnera. 2010. Human chitotriosidase polymorphism is associated with human longevity in Mediterranean nonagenarians and centenarians. Journal of Human Genetics 55: 8–12.

    Article  PubMed  CAS  Google Scholar 

  42. Di Rosa, M., K. Mangano, C. De Gregorio, F. Nicoletti, and L. Malaguarnera. 2012. Association of chitotriosidase genotype with the development of non-alcoholic fatty liver disease. Hepatology Research. doi: 10.1111/j.1872-034X.2012.01063.x

  43. Hu, B., K. Trinh, W.F. Figueiira, and P.A. Price. 1996. Isolation and sequence of a novel human chondrocyte protein related to mammalian members of the chitinase protein family. Journal of Biological Chemistry 271: 19415–19420.

    Article  PubMed  CAS  Google Scholar 

  44. Nishikawa, K.C., and A.J. Millis. 2003. gp38k (CHI3L1) is a novel adhesion and migration factor for vascular cells. Experimental Cell Research 287: 79–87.

    Article  PubMed  CAS  Google Scholar 

  45. Ku, B.M., Y.K. Lee, J. Ryu, J.Y. Jeong, J. Choi, K.M. Eun, H.Y. Shin, D.G. Kim, E.M. Hwang, J.C. Yoo, J.Y. Park, G.S. Roh, H.J. Kim, G.J. Cho, W.S. Choi, S.H. Paek, and S.S. Kang. 2011. CHI3L1 (YKL-40) is expressed in human gliomas and regulates the invasion, growth and survival of glioma cells. International Journal of Cancer 12: 1316–1326.

    Article  Google Scholar 

  46. Lee, C.G., C.A. Da Silva, C.S. Dela Cruz, F. Ahangari, B. Ma, M.J. Kang, C.H. He, S. Takyar, and J.A. Elias. 2011. Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. Annual Review of Physiology 73: 479–482.

    Article  PubMed  CAS  Google Scholar 

  47. Bara, I., A. Ozier, P.O. Girodet, G. Carvalho, J. Cattiaux, H. Begueret, M. Thumerel, O. Ousova, R. Kolbeck, A.J. Coyle, J. Woods, J.M. Tunon de Lara, R. Marthan, and P. Berger. 2012. Role of YKL-40 in bronchial smooth muscle remodeling in asthma. American Journal of Respiratory and Critical Care Medicine 185: 715–722.

    Article  PubMed  CAS  Google Scholar 

  48. Martinez, F.O., L. Helming, and S. Gordon. 2009. Alternative activation of macrophages: An immunologic functional perspective. Annual Review of Immunology 27: 451–483.

    Article  PubMed  CAS  Google Scholar 

  49. Wynn, T.A., and L. Barron. 2010. Macrophages: Master regulators of inflammation and fibrosis. Seminars in Liver Disease 30: 245–257.

    Article  PubMed  CAS  Google Scholar 

  50. Berry, A., P. Balard, A. Coste, D. Olagnier, C. Lagane, H. Authier, F. Benoit-Vical, J.C. Lepert, J.P. Séguéla, J.F. Magnaval, P. Chambon, D. Metzger, B. Desvergne, W. Wahli, J. Auwerx, and B. Pipy. 2007. IL-13 induces expression of CD36 in human monocytes through PPAR gamma activation. European Journal of Immunology 37: 1642–1652.

    Article  PubMed  CAS  Google Scholar 

  51. Kang, K., S.M. Reilly, V. Karabacak, M.R. Gangl, K. Fitzgerald, B. Hatano, and C.H. Lee. 2008. Adipocyte-derived Th2 cytokines and myeloid PPAR delta regulate macrophage polarization and insulin sensitivity. Cell Metabolism 7: 485–495.

    Article  PubMed  CAS  Google Scholar 

  52. Pourcet, B., J.E. Feig, Y. Vengrenyuk, A. Hobbs, D. Kepka-Lenhart, M. Garabedian, S.M. Jr, E.A. Fisher Morris and I. Pineda-Torra. 2011. LXR{alpha} regulates macrophage arginase 1 through PU.1 and interferon regulatory factor 8. Circulation Research 109: 492–501.

    Article  PubMed  CAS  Google Scholar 

  53. Berres, M.L., S. Papen, K. Pauels, P. Schmitz, M.M. Zaldivar, C. Hellerbrand, T. Mueller, T. Berg, R. Weiskirchen, C. Trautwein, and H.E. Wasmuth. 2009. A functional variation in CHI3L1 is associated with severity of liver fibrosis and YKL40 serum levels in chronic hepatitis C infection. Journal of Hepatology 50: 370–376.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Giulia Malaguarnera is supported by the International Ph.D. Program in Neuropharmacology (Coordinator Prof. Filippo Drago), University of Catania Medical School, Catania, Italy. We thank Dr. Filomena Biazzo and Dr. Michele Tuttobene of the Transfusional Centre “Garibaldi” Hospital, Catania, S. Immuno-Haematology and Transfusional Medicine, for providing the buffy coats.

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Di Rosa, M., Malaguarnera, G., De Gregorio, C. et al. Evaluation of CHI3L-1 and CHIT-1 Expression in Differentiated and Polarized Macrophages. Inflammation 36, 482–492 (2013). https://doi.org/10.1007/s10753-012-9569-8

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