Granulocytes Negatively Regulate Secretion of Transforming Growth Factor β1 by Bone Marrow Mononuclear Cells via Secretion of Erythropoietin Receptors in the Milieu
Tóm tắt
In my previous study, I demonstrated that bone marrow-derived mononuclear cells (BM MNCs) secrete copious amounts of Transforming Growth Factor β1 (TGFβ1) in response to erythropoietin (EPO). In this study, I investigated the principal cell type involved in the process. I found that a large percentage of various marrow cells, but not their mature counterparts present in the peripheral blood, express EPO-receptors (EPO-R). Cell depletion experiments showed that depletion of Glycophorin positive erythroblasts and CD41+ megakaryocytes – the prime suspects – did not affect the EPO-mediated TGFβ1 secretion by the BM MNCs. However, individual depletion of CD2+ T lymphocytes, CD14+ monocyte/macrophages, and CD19+ B cells affected the TGFβ1 secretion by EPO-primed MNCs: depletion of CD2+ cells had the most striking effect. Unexpectedly, and most interestingly, depletion of CD15+ granulocytes led to a significant increase in the TGFβ1 secretion by both naïve and EPO-primed BM MNCs, suggesting that these cells negatively regulate the process. Mechanistically, I show that the CD15+ cells exert this regulatory effect via secretion of both full-length and soluble EPO-R in the milieu. Overall my results, for the first time, unravel an in-built regulatory mechanism prevailing in the BM microenvironment that regulates the secretion of TGFβ1 by controlling EPO-EPO-R interaction. My data could be relevant in understanding the pathophysiology of several conditions associated with deregulated production of TGFβ1 in the marrow compartment.
Tài liệu tham khảo
Kale, V. P. (2004). Differential activation of MAPK signaling pathways by TGF-beta1 forms the molecular mechanism behind its dose-dependent bidirectional effects on hematopoiesis. Stem cells and development, 13(1), 27–38. https://doi.org/10.1089/154732804773099236
Kale, V. P., & Vaidya, A. A. (2004). Molecular mechanisms behind the dose-dependent differential activation of MAPK pathways induced by transforming growth factor-beta1 in hematopoietic cells. Stem cells and development, 13(5), 536–547. https://doi.org/10.1089/scd.2004.13.536
Blank, U., & Karlsson, S. (2015). TGF-β signaling in the control of hematopoietic stem cells. Blood, 125(23), 3542–3550. https://doi.org/10.1182/blood-2014-12-618090
Kale, V. P. (2020). Transforming growth factor-β boosts the functionality of human bone marrow-derived mesenchymal stromal cells. Cell biology international, 44(11), 2293–2306. https://doi.org/10.1002/cbin.11437
Wang, X., Dong, F., Zhang, S., Yang, W., Yu, W., Wang, Z., Zhang, S., Wang, J., Ma, S., Wu, P., Gao, Y., Dong, J., Tang, F., Cheng, T., & Ema, H. (2018). TGF-β1 Negatively Regulates the Number and Function of Hematopoietic Stem Cells. Stem cell reports, 11(1), 274–287. https://doi.org/10.1016/j.stemcr.2018.05.017
Naka, K., & Hirao, A. (2017). Regulation of Hematopoiesis and Hematological Disease by TGF-β Family Signaling Molecules. Cold Spring Harbor perspectives in biology, 9(9), a027987. https://doi.org/10.1101/cshperspect.a027987
Kuhikar, R., Khan, N., Philip, J., Melinkeri, S., Kale, V., & Limaye, L. (2020). Transforming growth factor β1 accelerates and enhances in vitro red blood cell formation from hematopoietic stem cells by stimulating mitophagy. Stem cell research & therapy, 11(1), 71. https://doi.org/10.1186/s13287-020-01603-z
Rameshwar, P., Chang, V. T., Thacker, U. F., & Gascón, P. (1998). Systemic transforming growth factor-beta in patients with bone marrow fibrosis--pathophysiological implications. American journal of hematology, 59(2), 133–142. https://doi.org/10.1002/(sici)1096-8652(199810)59:2<133::aid-ajh6>3.0.co;2-z
Chagraoui, H., Komura, E., Tulliez, M., Giraudier, S., Vainchenker, W., & Wendling, F. (2002). Prominent role of TGF-beta 1 in thrombopoietin-induced myelofibrosis in mice. Blood, 100(10), 3495–3503. https://doi.org/10.1182/blood-2002-04-1133
Agarwal, A., Morrone, K., Bartenstein, M., Zhao, Z. J., Verma, A., & Goel, S. (2016). Bone marrow fibrosis in primary myelofibrosis: pathogenic mechanisms and the role of TGF-β. Stem cell investigation, 3, 5. https://doi.org/10.3978/j.issn.2306-9759.2016.02.03
Lisowska, K. A., Debska-Slizień, A., Bryl, E., Rutkowski, B., & Witkowski, J. M. (2010). Erythropoietin receptor is expressed on human peripheral blood T and B lymphocytes and monocytes and is modulated by recombinant human erythropoietin treatment. Artificial organs, 34(8), 654–662. https://doi.org/10.1111/j.1525-1594.2009.00948.x
Lisowska, K. A., Bryl, E., & Witkowski, J. M. (2011). Erythropoietin receptor is detectable on peripheral blood lymphocytes and its expression increases in activated T lymphocytes. Haematologica, 96(3), e12–e14. https://doi.org/10.3324/haematol.2010.038414
Deshet-Unger, N., Kolomansky, A., Ben-Califa, N., Hiram-Bab, S., Gilboa, D., Liron, T., Ibrahim, M., Awida, Z., Gorodov, A., Oster, H. S., Mittelman, M., Rauner, M., Wielockx, B., Gabet, Y., & Neumann, D. (2020). Erythropoietin receptor in B cells plays a role in bone remodeling in mice. Theranostics, 10(19), 8744–8756. https://doi.org/10.7150/thno.45845
Rocchetta, F., Solini, S., Mister, M., Mele, C., Cassis, P., Noris, M., Remuzzi, G., & Aiello, S. (2011). Erythropoietin enhances immunostimulatory properties of immature dendritic cells. Clinical and experimental immunology, 165(2), 202–210. https://doi.org/10.1111/j.1365-2249.2011.04417.x
Li, W., Wang, Y., Zhao, H., Zhang, H., Xu, Y., Wang, S., Guo, X., Huang, Y., Zhang, S., Han, Y., Wu, X., Rice, C. M., Huang, G., Gallagher, P. G., Mendelson, A., Yazdanbakhsh, K., Liu, J., Chen, L., & An, X. (2019). Identification and transcriptome analysis of erythroblastic island macrophages. Blood, 134(5), 480–491. https://doi.org/10.1182/blood.2019000430
Lappin, K. M., Mills, K. I., & Lappin, T. R. (2021). Erythropoietin in bone homeostasis-Implications for efficacious anemia therapy. Stem cells translational medicine, 10(6), 836–843. https://doi.org/10.1002/sctm.20-0387
McGee, S. J., Havens, A. M., Shiozawa, Y., Jung, Y., & Taichman, R. S. (2012). Effects of erythropoietin on the bone microenvironment. Growth factors (Chur, Switzerland), 30(1), 22–28. https://doi.org/10.3109/08977194.2011.637034
Arcasoy, M. O. (2008). The non-haematopoietic biological effects of erythropoietin. British journal of haematology, 141(1), 14–31. https://doi.org/10.1111/j.1365-2141.2008.07014.x
Gong, Y., Zhao, M., Yang, W., Gao, A., Yin, X., Hu, L., Wang, X., Xu, J., Hao, S., Cheng, T., & Cheng, H. (2018). Megakaryocyte-derived excessive transforming growth factor β1 inhibits proliferation of normal hematopoietic stem cells in acute myeloid leukemia. Experimental hematology, 60, 40–46.e2. https://doi.org/10.1016/j.exphem.2017.12.01
Arcasoy, M. O. (2010). Non-erythroid effects of erythropoietin. Haematologica, 95(11), 1803–1805. https://doi.org/10.3324/haematol.2010.030213
Elliott, S., Busse, L., Swift, S., McCaffery, I., Rossi, J., Kassner, P., & Begley, C. G. (2012). Lack of expression and function of erythropoietin receptors in the kidney. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 27(7), 2733–2745. https://doi.org/10.1093/ndt/gfr698
Elliott, S., & Sinclair, A. M. (2012). The effect of erythropoietin on normal and neoplastic cells. Biologics : targets & therapy, 6, 163–189. https://doi.org/10.2147/BTT.S32281
Takeshita, A., Shinjo, K., Naito, K., Ohnishi, K., Higuchi, M., & Ohno, R. (2002). Erythropoietin receptor in myelodysplastic syndrome and leukemia. Leukemia & lymphoma, 43(2), 261–264. https://doi.org/10.1080/10428190290006026
Celebi, H., Akan, H., Akçağlayan, E., Ustün, C., & Arat, M. (2000). Febrile neutropenia in allogeneic and autologous peripheral blood stem cell transplantation and conventional chemotherapy for malignancies. Bone marrow transplantation, 26(2), 211–214. https://doi.org/10.1038/sj.bmt.1702503
Lisowska, K. A., Bryl, E., & Witkowski, J. M. (2011). Erythropoietin receptor is detectable on peripheral blood lymphocytes and its expression increases in activated T lymphocytes. Haematologica, 96(3), e12–e14. https://doi.org/10.3324/haematol.2010.038414
Mausberg, A. K., Meyer Zu Hörste, G., Dehmel, T., Stettner, M., Lehmann, H. C., Sheikh, K. A., & Kieseier, B. C. (2011). Erythropoietin ameliorates rat experimental autoimmune neuritis by inducing transforming growth factor-β in macrophages. PloS one, 6(10), e26280. https://doi.org/10.1371/journal.pone.0026280
Lifshitz, L., Tabak, G., Gassmann, M., Mittelman, M., & Neumann, D. (2010). Macrophages as novel target cells for erythropoietin. Haematologica, 95(11), 1823–1831. https://doi.org/10.3324/haematol.2010.025015
Prutchi-Sagiv, S., Golishevsky, N., Oster, H. S., Katz, O., Cohen, A., Naparstek, E., Neumann, D., & Mittelman, M. (2006). Erythropoietin treatment in advanced multiple myeloma is associated with improved immunological functions: could it be beneficial in early disease? British journal of haematology, 135(5), 660–672. https://doi.org/10.1111/j.1365-2141.2006.06366.x
Binder, C., Cvetkovski, F., Sellberg, F., Berg, S., Paternina Visbal, H., Sachs, D. H., Berglund, E., & Berglund, D. (2020). CD2 Immunobiology. Frontiers in immunology, 11, 1090. https://doi.org/10.3389/fimmu.2020.01090
Sanjabi, S., Oh, S. A., & Li, M. O. (2017). Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection. Cold Spring Harbor perspectives in biology, 9(6), a022236. https://doi.org/10.1101/cshperspect.a022236Peng et al., 2020 Cell Death and Disease.
Peng, B., Kong, G., Yang, C., & Ming, Y. (2020). Erythropoietin and its derivatives: from tissue protection to immune regulation. Cell death & disease, 11(2), 79. https://doi.org/10.1038/s41419-020-2276-8