REGULATION OF INNATE IMMUNE CELLS BY POLYAMINES: A REVIEW
Keywords:
Polyamines, innate immune response, Innate immune cells, regulation, epithelial cells
Abstract
Polyamines, including spermine, spermidine, and putrescine, are small aliphatic cations essential for cellular growth, differentiation, and survival. Emerging evidence highlights their crucial role in regulating innate immune cells, where they modulate both protective and suppressive functions. In neutrophils, polyamines influence the formation and structural integrity of extracellular traps (NETs). In macrophages, they regulate polarization between pro-inflammatory M1 and anti-inflammatory M2 phenotypes, affecting immune responses in infection and tumor contexts. Mast cells, eosinophils, and basophils rely on polyamines for mediator release, granule maintenance, adhesion, and survival. In natural killer (NK) cells, polyamines can suppress cytotoxic activity by reducing receptor expression and effector molecule production, while also supporting maturation and proliferation through IL-2 modulation. In dendritic cells, polyamines promote a tolerogenic phenotype via IL-10 production and generate reactive oxygen species that inhibit maturation and antigen presentation. In epithelial cells, polyamines sustain TLR2 expression and barrier integrity, supporting mucosal immune homeostasis. Importantly, polyamines act as a double-edged sword, either enhancing or suppressing immune responses depending on cell type, microenvironment, and concentration. Dysregulated polyamine metabolism contributes to impaired innate immunity, chronic inflammation, and tumor immune evasion. Understanding these multifaceted roles offers potential therapeutic strategies for modulating innate immune function in disease.
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References
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7. Brinkmann, V., Reichard, U., Goosmann, C., Fauler, B., Uhlemann, Y., Weiss, D. S., ... & Zychlinsky, A. (2004). Neutrophil extracellular traps kill bacteria. science, 303(5663), 1532-1535.
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9. Casero Jr, R. A., & Pegg, A. E. (2009). Polyamine catabolism and disease. Biochemical Journal, 421(3), 323-338.
10. Chamaillard, L., Catros-Quemener, V., Delcros, J. G., Bansard, J. Y., Havouis, R., Desury, D., ... & Moulinoux, J. P. (1997). Polyamine deprivation prevents the development of tumour-induced immune suppression. British journal of cancer, 76(3), 365-370.
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28. Kurosawa, M., Uno, D., Hanawa, K.,&Kobayashi, S. (1990). Polyamines stimulate the phosphorylation of phosphatidylinositol in rat mast cell granules. Allergy, 45(4), 262-267.
29. Latour, Y. L., Gobert, A. P.,&Wilson, K. T. (2020). The role of polyamines in the regulation of macrophage polarization and function. Amino Acids, 52(2), 151-160.
30. Leeuwenhoek, A. V. (1978). Observationes D. Anthonii Lewenhoeck, de natis è semine genitali animalculis. Philosophical Transactions of the Royal Society of London, 12(142), 1040-1046.
31. Levin, A. M., Bates, D. L., Ring, A. M., Krieg, C., Lin, J. T., Su, L., ...&Garcia, K. C. (2012). Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’. Nature, 484(7395), 529-533.
32. Liu, B., Jiang, X., Cai, L., Zhao, X., Dai, Z., Wu, G.,&Li, X. (2019). Putrescine mitigates intestinal atrophy through suppressing inflammatory response in weanling piglets. Journal of animal science and biotechnology, 10(1), 69.
33. Liu, L., Guo, X., Rao, J. N., Zou, T., Marasa, B. S., Chen, J., ...&Wang, J. Y. (2006). Polyamine-modulated c-Myc expression in normal intestinal epithelial cells regulates p21Cip1 transcription through a proximal promoter region. Biochemical Journal, 398(2), 257-267.
34. Liu, L., Li, L., Rao, J. N., Zou, T., Zhang, H. M., Boneva, D., ...&Wang, J. Y. (2005). Polyamine-modulated expression of c-myc plays a critical role in stimulation of normal intestinal epithelial cell proliferation. American Journal of Physiology-Cell Physiology, 288(1), C89-C99.
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36. Miller-Fleming, L., Olin-Sandoval, V., Campbell, K., & Ralser, M. (2015). Remaining mysteries of molecular biology: the role of polyamines in the cell. Journal of molecular biology, 427(21), 3389-3406.
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42. Paardekooper, L. M., Vos, W., & Van Den Bogaart, G. (2019). Oxygen in the tumor microenvironment: effects on dendritic cell function. Oncotarget, 10(8), 883.
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44. Pegg, A. E. (2009). Mammalian polyamine metabolism and function. IUBMB life, 61(9), 880-894.
45. Pegg, A. E. (2013). Toxicity of polyamines and their metabolic products. Chemical research in toxicology, 26(12), 1782-1800.
46. Pegg, A. E.,&McCann, P. P. (1982). Polyamine metabolism and function. American Journal of Physiology-Cell Physiology, 243(5), C212-C221.
47. Proietti, E., Rossini, S., Grohmann, U., & Mondanelli, G. (2020). Polyamines and kynurenines at the intersection of immune modulation. Trends in immunology, 41(11), 1037-1050.
48. Puleston, D. J., Baixauli, F., Sanin, D. E., Edwards-Hicks, J., Villa, M., Kabat, A. M., ...&Pearce, E. L. (2021). Polyamine metabolism is a central determinant of helper T cell lineage fidelity. Cell, 184(16), 4186-4202.
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50. Shapouri‐Moghaddam, A., Mohammadian, S., Vazini, H., Taghadosi, M., Esmaeili, S. A., Mardani, F., ... & Sahebkar, A. (2018). Macrophage plasticity, polarization, and function in health and disease. Journal of cellular physiology, 233(9), 6425-6440.
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54. Stoiber, W., Obermayer, A., Steinbacher, P., & Krautgartner, W. D. (2015). The role of reactive oxygen species (ROS) in the formation of extracellular traps (ETs) in humans. Biomolecules, 5(2), 702-723.
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2. Abreu, M. T., Fukata, M., & Arditi, M. (2005). TLR signaling in the gut in health and disease. The Journal of Immunology, 174(8), 4453-4460.
3. Åbrink, M., Grujic, M., & Pejler, G. (2004). Serglycin is essential for maturation of mast cell secretory granule. Journal of biological chemistry, 279(39), 40897-40905.
4. Anderson, K. V. (2000). Toll signaling pathways in the innate immune response. Current opinion in immunology, 12(1), 13-19.
5. Banchereau, J.,&Steinman, R. M. (1998). Dendritic cells and the control of immunity. Nature, 392(6673), 245-252.
6. Bowlin, T. L., McKown, B. J., & Sunkara, P. S. (1987). Increased ornithine decarboxylase activity and polyamine biosynthesis are required for optimal cytolytic T lymphocyte induction. Cellular immunology, 105(1), 110-117.
7. Brinkmann, V., Reichard, U., Goosmann, C., Fauler, B., Uhlemann, Y., Weiss, D. S., ... & Zychlinsky, A. (2004). Neutrophil extracellular traps kill bacteria. science, 303(5663), 1532-1535.
8. Carriche, G. M., Almeida, L., Stüve, P., Velasquez, L., Dhillon-LaBrooy, A., Roy, U., ... & Sparwasser, T. (2021). Regulating T-cell differentiation through the polyamine spermidine. Journal of Allergy and Clinical Immunology, 147(1), 335-348.
9. Casero Jr, R. A., & Pegg, A. E. (2009). Polyamine catabolism and disease. Biochemical Journal, 421(3), 323-338.
10. Chamaillard, L., Catros-Quemener, V., Delcros, J. G., Bansard, J. Y., Havouis, R., Desury, D., ... & Moulinoux, J. P. (1997). Polyamine deprivation prevents the development of tumour-induced immune suppression. British journal of cancer, 76(3), 365-370.
11. Chen, J., Rao, J. N., Zou, T., Liu, L., Marasa, B. S., Xiao, L., ...&Wang, J. Y. (2007). Polyamines are required for expression of Toll-like receptor 2 modulating intestinal epithelial barrier integrity. American Journal of Physiology-Gastrointestinal and Liver Physiology, 293(3), G568-G576.
12. Chougnet, C. A., Thacker, R. I., Shehata, H. M., Hennies, C. M., Lehn, M. A., Lages, C. S.,&Janssen, E. M. (2015). Loss of phagocytic and antigen cross-presenting capacity in aging dendritic cells is associated with mitochondrial dysfunction. The Journal of Immunology, 195(6), 2624-2632.
13. Csomós, K., Kristóf, E., Jakob, B., Csomós, I., Kovács, G., Rotem, O., Hodrea, J., Bagoly, Z., Muszbek, L., Balajthy, Z., Csősz, É., & Fésüs, L. (2016). Protein cross-linking by chlorinated polyamines and transglutamylation stabilizes neutrophil extracellular traps. Cell death&disease, 7(8), e2332. https://doi.org/10.1038/cddis.2016.200.
14. DD, M. (1997). Mast cells. Physiol Rev, 77, 1033-1079.
15. Fajardo, I., Urdiales, J. L., Medina, M. A., & Sanchez-Jimenez, F. (2001). Effects of phorbol ester and dexamethasone treatment on histidine decarboxylase and ornithine decarboxylase in basophilic cells. Biochemical pharmacology, 61(9), 1101-1106.
16. Flescher, E. L. I. E. Z. E. R., Bowlin, T. L., & Talal, N. O. R. M. A. N. (1989). Polyamine oxidation down-regulates IL-2 production by human peripheral blood mononuclear cells. The Journal of Immunology, 142(3), 907-912.
17. Fuertes, M. B., Kacha, A. K., Kline, J., Woo, S. R., Kranz, D. M., Murphy, K. M., & Gajewski, T. F. (2011). Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cells. Journal of Experimental Medicine, 208(10), 2005-2016.
18. Gabrilovich, D. I.,&Nagaraj, S. (2009). Myeloid-derived suppressor cells as regulators of the immune system. Nature reviews immunology, 9(3), 162-174.
19. Galli, S. J., Kalesnikoff, J., Grimbaldeston, M. A., Piliponsky, A. M., Williams, C. M., & Tsai, M. (2005). Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu. Rev. Immunol., 23(1), 749-786.
20. Galli, S. J., Nakae, S.,&Tsai, M. (2005). Mast cells in the development of adaptive immune responses. Nature immunology, 6(2), 135-142.
21. García-Faroldi, G., Rodríguez, C. E., Urdiales, J. L., Pérez-Pomares, J. M., Dávila, J. C., Pejler, G., ...&Fajardo, I. (2010). Polyamines are present in mast cell secretory granules and are important for granule homeostasis. PLoS One, 5(11), e15071.
22. Haskó, G., Kuhel, D. G., Marton, A., Nemeth, Z. H., Deitch, E. A., & Szabó, C. (2000). Spermine differentially regulates the production of interleukin-12 p40 and interleukin-10 and suppresses the release of the T helper 1 cytokine interferon-γ. Shock, 14(2), 144-149.
23. Hiltbold, E. M., Vlad, A. M., Ciborowski, P., Watkins, S. C.,&Finn, O. J. (2000). The mechanism of unresponsiveness to circulating tumor antigen MUC1 is a block in intracellular sorting and processing by dendritic cells. The Journal of Immunology, 165(7), 3730-3741.
24. Ilmarinen, P., Moilanen, E., Erjefält, J. S., & Kankaanranta, H. (2015). The polyamine spermine promotes survival and activation of human eosinophils. Journal of Allergy and Clinical Immunology, 136(2), 482-484.
25. Jain, V. (2018). Role of polyamines in asthma pathophysiology. Medical Sciences, 6(1), 4.
26. Janakiram, N. B., Mohammed, A., Bryant, T., Zhang, Y., Brewer, M., Duff, A., ... & Rao, C. V. (2016). Potentiating NK cell activity by combination of Rosuvastatin and Difluoromethylornithine for effective chemopreventive efficacy against Colon Cancer. Scientific reports, 6(1), 37046.
27. Kurosawa, M., Uno, D.,&Kobayashi, S. (1991). Naturally occurring aliphatic polyamines‐induced histamine release from rat peritoneal mast cells. Allergy, 46(5), 349-354.
28. Kurosawa, M., Uno, D., Hanawa, K.,&Kobayashi, S. (1990). Polyamines stimulate the phosphorylation of phosphatidylinositol in rat mast cell granules. Allergy, 45(4), 262-267.
29. Latour, Y. L., Gobert, A. P.,&Wilson, K. T. (2020). The role of polyamines in the regulation of macrophage polarization and function. Amino Acids, 52(2), 151-160.
30. Leeuwenhoek, A. V. (1978). Observationes D. Anthonii Lewenhoeck, de natis è semine genitali animalculis. Philosophical Transactions of the Royal Society of London, 12(142), 1040-1046.
31. Levin, A. M., Bates, D. L., Ring, A. M., Krieg, C., Lin, J. T., Su, L., ...&Garcia, K. C. (2012). Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’. Nature, 484(7395), 529-533.
32. Liu, B., Jiang, X., Cai, L., Zhao, X., Dai, Z., Wu, G.,&Li, X. (2019). Putrescine mitigates intestinal atrophy through suppressing inflammatory response in weanling piglets. Journal of animal science and biotechnology, 10(1), 69.
33. Liu, L., Guo, X., Rao, J. N., Zou, T., Marasa, B. S., Chen, J., ...&Wang, J. Y. (2006). Polyamine-modulated c-Myc expression in normal intestinal epithelial cells regulates p21Cip1 transcription through a proximal promoter region. Biochemical Journal, 398(2), 257-267.
34. Liu, L., Li, L., Rao, J. N., Zou, T., Zhang, H. M., Boneva, D., ...&Wang, J. Y. (2005). Polyamine-modulated expression of c-myc plays a critical role in stimulation of normal intestinal epithelial cell proliferation. American Journal of Physiology-Cell Physiology, 288(1), C89-C99.
35. Mandal, S., Mandal, A., & Park, M. H. (2015). Depletion of the polyamines spermidine and spermine by overexpression of spermidine/spermine N 1-acetyltransferase 1 (SAT1) leads to mitochondria-mediated apoptosis in mammalian cells. Biochemical Journal, 468(3), 435-447.
36. Miller-Fleming, L., Olin-Sandoval, V., Campbell, K., & Ralser, M. (2015). Remaining mysteries of molecular biology: the role of polyamines in the cell. Journal of molecular biology, 427(21), 3389-3406.
37. Mondanelli, G., Ugel, S., Grohmann, U.,&Bronte, V. (2017). The immune regulation in cancer by the amino acid metabolizing enzymes ARG and IDO. Current opinion in pharmacology, 35, 30-39.
38. Murray, P. J.,&Wynn, T. A. (2011). Protective and pathogenic functions of macrophage subsets. Nature reviews immunology, 11(11), 723-737.
39. Murray, P. J.,&Wynn, T. A. (2011). Protective and pathogenic functions of macrophage subsets. Nature reviews immunology, 11(11), 723-737.
40. Najafi, M., Hashemi Goradel, N., Farhood, B., Salehi, E., Nashtaei, M. S., Khanlarkhani, N., ... & Mortezaee, K. (2019). Macrophage polarity in cancer: a review. Journal of cellular biochemistry, 120(3), 2756-2765.
41. Nakanishi, S.,&Cleveland, J. L. (2021). Polyamine homeostasis in development and disease. Medical Sciences, 9(2), 28.
42. Paardekooper, L. M., Vos, W., & Van Den Bogaart, G. (2019). Oxygen in the tumor microenvironment: effects on dendritic cell function. Oncotarget, 10(8), 883.
43. Pasquali, J. L., Mamont, P. S., Weryha, A., Knapp, A. M., Blervaque, A., & Siat, M. (1988). Immunosuppressive effects of (2R, 5R)-6-heptyne-2, 5-diamine an inhibitor of polyamine synthesis: I. effects on mitogen-induced immunoglobulin production in human cultured lymphocytes. Clinical and experimental immunology, 72(1), 141.
44. Pegg, A. E. (2009). Mammalian polyamine metabolism and function. IUBMB life, 61(9), 880-894.
45. Pegg, A. E. (2013). Toxicity of polyamines and their metabolic products. Chemical research in toxicology, 26(12), 1782-1800.
46. Pegg, A. E.,&McCann, P. P. (1982). Polyamine metabolism and function. American Journal of Physiology-Cell Physiology, 243(5), C212-C221.
47. Proietti, E., Rossini, S., Grohmann, U., & Mondanelli, G. (2020). Polyamines and kynurenines at the intersection of immune modulation. Trends in immunology, 41(11), 1037-1050.
48. Puleston, D. J., Baixauli, F., Sanin, D. E., Edwards-Hicks, J., Villa, M., Kabat, A. M., ...&Pearce, E. L. (2021). Polyamine metabolism is a central determinant of helper T cell lineage fidelity. Cell, 184(16), 4186-4202.
49. Schlitzer, A., McGovern, N., & Ginhoux, F. (2015, May). Dendritic cells and monocyte-derived cells: Two complementary and integrated functional systems. In Seminars in cell&developmental biology (Vol. 41, pp. 9-22). Academic Press.
50. Shapouri‐Moghaddam, A., Mohammadian, S., Vazini, H., Taghadosi, M., Esmaeili, S. A., Mardani, F., ... & Sahebkar, A. (2018). Macrophage plasticity, polarization, and function in health and disease. Journal of cellular physiology, 233(9), 6425-6440.
51. Sitaraman, S. V., Merlin, D., Wang, L., Wong, M., Gewirtz, A. T., Si-Tahar, M., & Madara, J. L. (2001). Neutrophil-epithelial crosstalk at the intestinal lumenal surface mediated by reciprocal secretion of adenosine and IL-6. The Journal of clinical investigation, 107(7), 861-869.
52. Soda, K., Kano, Y., Nakamura, T., Kasono, K., Kawakami, M., & Konishi, F. (2005). Spermine, a natural polyamine, suppresses LFA-1 expression on human lymphocyte. The Journal of Immunology, 175(1), 237-245.
53. Stevens, R. L.,&Austen, K. F. (1989). Recent advances in the cellular and molecular biology of mast cells. Immunology today, 10(11), 381-386.
54. Stoiber, W., Obermayer, A., Steinbacher, P., & Krautgartner, W. D. (2015). The role of reactive oxygen species (ROS) in the formation of extracellular traps (ETs) in humans. Biomolecules, 5(2), 702-723.
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Published
2026-04-07
How to Cite
Saif Mazeel Abed, & Zahra Hamza Ali. (2026). REGULATION OF INNATE IMMUNE CELLS BY POLYAMINES: A REVIEW. IJRDO - JOURNAL OF BIOLOGICAL SCIENCE, 12(1), 12-17. https://doi.org/10.69980/bs.v12i1.6623
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Articles
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