Abstract
Evidence has shown that inflammation acts as a critical contributor to the pathogenesis of intracranial aneurysm (IA), a potentially devastating clinical problem. T cell immunoglobulin and mucin protein 3 (Tim-3) is a negative regulatory molecule and plays important roles in the inflammation process. In the current study, we investigated the expression of Tim-3 and its correlation with tumor necrosis factor alpha (TNF-α) in IA patients. Data showed that both messenger RNA (mRNA) level and protein level of Tim-3 were significantly decreased in CD4+ T cells and CD8+ T cells from IA patients than from healthy controls (P < 0.001). However, expression of Tim-3 was not altered in monocytes between patients and healthy donors. Further analyses revealed that patients with ruptured aneurysm had significantly lower level of Tim-3 in CD8+ T cells than those with un-ruptured aneurysm. In addition, a negative correlation between serum level of TNF-α and the expression of Tim-3 in CD4+ T cells was observed in IA patients. Similar correlation was also identified in CD8+ T cells from IA patients. Our study suggests that Tim-3 may participate in the development and progression of IA by probably its negative regulation on TNF-α.
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Zhang, H.F., M.G. Zhao, G.B. Liang, Z.Q. Song, and Z.Q. Li. 2013. Expression of pro-inflammatory cytokines and the risk of intracranial aneurysm. Inflammation 36: 1195–1200.
Chalouhi, N., Ali, M. S., Jabbour, P. M., Tjoumakaris, S. I., Gonzalez, L. F., Rosenwasser, R. H., Koch, W. J., and Dumont, A. S. (2012) Biology of intracranial aneurysms: Role of inflammation. Journal of cerebral blood flow and metabolism: Official journal of the International Society of Cerebral Blood Flow and Metabolism 32, 1659–1676
Jayaraman, T., A. Paget, Y.S. Shin, X. Li, J. Mayer, H. Chaudhry, Y. Niimi, M. Silane, and A. Berenstein. 2008. TNF-alpha-mediated inflammation in cerebral aneurysms: A potential link to growth and rupture. Vascular Health and Risk Management 4: 805–817.
Turjman, A.S., F. Turjman, and E.R. Edelman. 2014. Role of fluid dynamics and inflammation in intracranial aneurysm formation. Circulation 129: 373–382.
Monney, L., C.A. Sabatos, J.L. Gaglia, A. Ryu, H. Waldner, T. Chernova, S. Manning, E.A. Greenfield, A.J. Coyle, R.A. Sobel, G.J. Freeman, and V.K. Kuchroo. 2002. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415: 536–541.
Sanchez-Fueyo, A., J. Tian, D. Picarella, C. Domenig, X.X. Zheng, C.A. Sabatos, N. Manlongat, O. Bender, T. Kamradt, V.K. Kuchroo, J.C. Gutierrez-Ramos, A.J. Coyle, and T.B. Strom. 2003. Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nature Immunology 4: 1093–1101.
Khademi, M., Illes, Z., Gielen, A. W., Marta, M., Takazawa, N., Baecher-Allan, C., Brundin, L., Hannerz, J., Martin, C., Harris, R. A., Hafler, D. A., Kuchroo, V. K., Olsson, T., Piehl, F., and Wallstrom, E. (2004) T Cell Ig- and mucin-domain-containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis. Journal of immunology (Baltimore, Md. : 1950) 172, 7169–7176
Simmons, W. J., Koneru, M., Mohindru, M., Thomas, R., Cutro, S., Singh, P., Dekruyff, R. H., Inghirami, G., Coyle, A. J., Kim, B. S., and Ponzio, N. M. (2005) Tim-3+ T-bet + tumor-specific Th1 cells colocalize with and inhibit development and growth of murine neoplasms. Journal of immunology (Baltimore, Md. : 1950) 174, 1405–1415
Han, G., Chen, G., Shen, B., and Li, Y. (2013) Tim-3: An activation marker and activation limiter of innate immune cells. Frontiers in immunology 4, 449
Cao, E., X. Zang, U.A. Ramagopal, A. Mukhopadhaya, A. Fedorov, E. Fedorov, W.D. Zencheck, J.W. Lary, J.L. Cole, H. Deng, H. Xiao, T.P. Dilorenzo, J.P. Allison, S.G. Nathenson, and S.C. Almo. 2007. T cell immunoglobulin mucin-3 crystal structure reveals a galectin-9-independent ligand-binding surface. Immunity 26: 311–321.
Hansen, J.A., S.M. Hanash, L. Tabellini, C. Baik, R.L. Lawler, B.M. Grogan, B. Storer, A. Chin, M. Johnson, C.H. Wong, Q. Zhang, P.J. Martin, and G.B. McDonald. 2013. A novel soluble form of Tim-3 associated with severe graft-versus-host disease. Biology of blood and marrow transplantation: Journal of the American Society for Blood and Marrow Transplantation 19: 1323–1330.
Veenstra, R.G., P.A. Taylor, Q. Zhou, A. Panoskaltsis-Mortari, M. Hirashima, R. Flynn, D. Liu, A.C. Anderson, T.B. Strom, V.K. Kuchroo, and B.R. Blazar. 2012. Contrasting acute graft-versus-host disease effects of Tim-3/galectin-9 pathway blockade dependent upon the presence of donor regulatory T cells. Blood 120: 682–690.
Li, S., W. Liao, M. Chen, S. Shan, Y. Song, S. Zhang, H. Song, and Z. Yuan. 2014. Expression of programmed death-1 (PD-1) on CD4+ and CD8+ T cells in rheumatoid arthritis. Inflammation.
Li, S., Peng, D., He, Y., Zhang, H., Sun, H., Shan, S., Song, Y., Zhang, S., Xiao, H., Song, H., and Zhang, M. (2014) Expression of TIM-3 on CD4+ and CD8+ T cells in the peripheral blood and synovial fluid of rheumatoid arthritis. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica doi: 10.1111/apm.12228
Wang, M., Ji, B., Wang, J., Cheng, X., Zhou, Q., Zhou, J., Cao, C., and Guo, Q. (2014) Tim-3 polymorphism downregulates gene expression and is involved in the susceptibility to ankylosing spondylitis. DNA and cell biology doi: 10.1089/dna.2014.2456
Lee, J., J.M. Oh, J.W. Hwang, J.K. Ahn, E.K. Bae, J. Won, E.M. Koh, and H.S. Cha. 2011. Expression of human TIM-3 and its correlation with disease activity in rheumatoid arthritis. Scandinavian Journal of Rheumatology 40: 334–340.
Wu, J., C. Liu, S. Qian, and H. Hou. 2013. The expression of Tim-3 in peripheral blood of ovarian cancer. DNA and Cell Biology 32: 648–653.
Han, S., S. Feng, L. Xu, W. Shi, X. Wang, H. Wang, C. Yu, T. Dong, M. Xu, and G. Liang. 2014. Tim-3 on peripheral CD4 (+) and CD8 (+) T cells is involved in the development of glioma. DNA and Cell Biology 33: 245–250.
Rong, Y.H., Z.H. Wan, H. Song, Y.L. Li, B. Zhu, H. Zang, Y. Zhao, H.L. Liu, A.M. Zhang, L. Xiao, S.J. Xin, and S.L. You. 2014. Tim-3 expression on peripheral monocytes and CD3 + CD16/CD56 + natural killer-like T cells in patients with chronic hepatitis B. Tissue Antigens 83: 76–81.
Su, E.W., J.Y. Lin, and L.P. Kane. 2008. TIM-1 and TIM-3 proteins in immune regulation. Cytokine 44: 9–13.
Anderson, A.C., D.E. Anderson, L. Bregoli, W.D. Hastings, N. Kassam, C. Lei, R. Chandwaskar, J. Karman, E.W. Su, M. Hirashima, J.N. Bruce, L.P. Kane, V.K. Kuchroo, and D.A. Hafler. 2007. Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science 318: 1141–1143.
Nakayama, M., H. Akiba, K. Takeda, Y. Kojima, M. Hashiguchi, M. Azuma, H. Yagita, and K. Okumura. 2009. Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood 113: 3821–3830.
Aoki, T., Fukuda, M., Nishimura, M., Nozaki, K., and Narumiya, S. (2014) Critical role of TNF-alpha-TNFR1 signaling in intracranial aneurysm formation. Acta neuropathologica communications 2, 34
Ali, M. S., Starke, R. M., Jabbour, P. M., Tjoumakaris, S. I., Gonzalez, L. F., Rosenwasser, R. H., Owens, G. K., Koch, W. J., Greig, N. H., and Dumont, A. S. (2013) TNF-alpha induces phenotypic modulation in cerebral vascular smooth muscle cells: Implications for cerebral aneurysm pathology. Journal of cerebral blood flow and metabolism: Official journal of the International Society of Cerebral Blood Flow and Metabolism 33, 1564–1573
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Hai-Feng Zhang and Ming-Guang Zhao contributed equally to this work.
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Zhang, HF., Zhao, MG., Liang, GB. et al. Downregulation of T Cell Immunoglobulin and Mucin Protein 3 in the Pathogenesis of Intracranial Aneurysm. Inflammation 38, 368–374 (2015). https://doi.org/10.1007/s10753-014-0040-x
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DOI: https://doi.org/10.1007/s10753-014-0040-x