Interleukin-7 receptor blockade suppresses adaptive and innate inflammatory responses in experimental colitis
Tóm tắt
Interleukin-7 (IL-7) acts primarily on T cells to promote their differentiation, survival, and homeostasis. Under disease conditions, IL-7 mediates inflammation through several mechanisms and cell types. In humans, IL-7 and its receptor (IL-7R) are increased in diseases characterized by inflammation such as atherosclerosis, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease. In mice, overexpression of IL-7 results in chronic colitis, and T-cell adoptive transfer studies suggest that memory T cells expressing high amounts of IL-7R drive colitis and are maintained and expanded with IL-7. The studies presented here were undertaken to better understand the contribution of IL-7R in inflammatory bowel disease in which colitis was induced with a bacterial trigger rather than with adoptive transfer. We examined the contribution of IL-7R on inflammation and disease development in two models of experimental colitis: Helicobacter bilis (Hb)-induced colitis in immune-sufficient Mdr1a−/− mice and in T- and B-cell-deficient Rag2−/− mice. We used pharmacological blockade of IL-7R to understand the mechanisms involved in IL-7R-mediated inflammatory bowel disease by analyzing immune cell profiles, circulating and colon proteins, and colon gene expression. Treatment of mice with an anti-IL-7R antibody was effective in reducing colitis in Hb-infected Mdr1a−/− mice by reducing T-cell numbers as well as T-cell function. Down regulation of the innate immune response was also detected in Hb-infected Mdr1a−/− mice treated with an anti-IL-7R antibody. In Rag2−/− mice where colitis was triggered by Hb-infection, treatment with an anti-IL-7R antibody controlled innate inflammatory responses by reducing macrophage and dendritic cell numbers and their activity. Results from our studies showed that inhibition of IL-7R successfully ameliorated inflammation and disease development in Hb-infected mice by controlling the expansion of multiple leukocyte populations, as well as the activity of these immune cells. Our findings demonstrate an important function of IL-7R-driven immunity in experimental colitis and indicate that the therapeutic efficacy of IL-7R blockade involves affecting both adaptive and innate immunity.
Tài liệu tham khảo
Di Sabatino A, Biancheri P, Rovedatti L, Macdonald TT, Corazza GR: New pathogenic paradigms in inflammatory bowel disease. Inflamm Bowel Dis. 2012, 18: 368-371. 10.1002/ibd.21735.
Ma A, Koka R, Burkett P: Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annu Rev Immunol. 2006, 24: 657-679. 10.1146/annurev.immunol.24.021605.090727.
Watanabe M, Watanabe N, Iwao Y, Ogata H, Kanai T, Ueno Y, Tsuchiya M, Ishii H, Aiso S, Habu S, Hibi T: The serum factor from patients with ulcerative colitis that induces T cell proliferation in the mouse thymus is interleukin-7. J Clin Immunol. 1997, 17: 282-292. 10.1023/A:1027322631036.
Kader HA, Tchernev VT, Satyaraj E, Lejnine S, Kotler G, Kingsmore SF, Patel DD: Protein microarray analysis of disease activity in pediatric inflammatory bowel disease demonstrates elevated serum PLGF, IL-7, TGF-beta1, and IL-12p40 levels in Crohn's disease and ulcerative colitis patients in remission versus active disease. Am J Gastroenterol. 2005, 100: 414-423. 10.1111/j.1572-0241.2005.40819.x.
Futagami S, Hiratsuka T, Suzuki K, Kusunoki M, Wada K, Miyake K, Ohashi K, Shimizu M, Takahashi H, Gudis K: Gammadelta T cells increase with gastric mucosal interleukin (IL)-7, IL-1beta, and Helicobacter pylori urease specific immunoglobulin levels via CCR2 upregulation in Helicobacter pylori gastritis. J Gastroenterol Hepatol. 2006, 21: 32-40. 10.1111/j.1440-1746.2005.04148.x.
Anderson CA, Boucher G, Lees CW, Franke A, D'Amato M, Taylor KD, Lee JC, Goyette P, Imielinski M, Latiano A: Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011, 43: 246-252. 10.1038/ng.764.
Watanabe M, Ueno Y, Yajima T, Okamoto S, Hayashi T, Yamazaki M, Iwao Y, Ishii H, Habu S, Uehira M: Interleukin 7 transgenic mice develop chronic colitis with decreased interleukin 7 protein accumulation in the colonic mucosa. J Exp Med. 1998, 187: 389-402. 10.1084/jem.187.3.389.
von Freeden-Jeffry U, Davidson N, Wiler R, Fort M, Burdach S, Murray R: IL-7 deficiency prevents development of a non-T cell non-B cell-mediated colitis. J Immunol. 1998, 161: 5673-5680.
Okada E, Yamazaki M, Tanabe M, Takeuchi T, Nanno M, Oshima S, Okamoto R, Tsuchiya K, Nakamura T, Kanai T: IL-7 exacerbates chronic colitis with expansion of memory IL-7Rhigh CD4+ mucosal T cells in mice. Am J Physiol Gastrointest Liver Physiol. 2005, 288: G745-G754. 10.1152/ajpgi.00276.2004.
Yamazaki M, Yajima T, Tanabe M, Fukui K, Okada E, Okamoto R, Oshima S, Nakamura T, Kanai T, Uehira M: Mucosal T cells expressing high levels of IL-7 receptor are potential targets for treatment of chronic colitis. J Immunol. 2003, 171: 1556-1563.
Maggio-Price L, Shows D, Waggie K, Burich A, Zeng W, Escobar S, Morrissey P, Viney JL: Helicobacter bilis infection accelerates and H. hepaticus infection delays the development of colitis in multiple drug resistance-deficient (mdr1a−/−) mice. Am J Pathol. 2002, 160: 739-751. 10.1016/S0002-9440(10)64894-8.
Maggio-Price L, Bielefeldt-Ohmann H, Treuting P, Iritani BM, Zeng W, Nicks A, Tsang M, Shows D, Morrissey P, Viney JL: Dual infection with Helicobacter bilis and Helicobacter hepaticus in p-glycoprotein-deficient mdr1a−/− mice results in colitis that progresses to dysplasia. Am J Pathol. 2005, 166: 1793-1806. 10.1016/S0002-9440(10)62489-3.
Burich A, Hershberg R, Waggie K, Zeng W, Brabb T, Westrich G, Viney JL, Maggio-Price L: Helicobacter-induced inflammatory bowel disease in IL-10- and T cell-deficient mice. Am J Physiol Gastrointest Liver Physiol. 2001, 281: G764-G778.
Brabb T, von Dassow P, Ordonez N, Schnabel B, Duke B, Goverman J: In situ tolerance within the central nervous system as a mechanism for preventing autoimmunity. J Exp Med. 2000, 192: 871-880.
Totsuka T, Kanai T, Nemoto Y, Makita S, Okamoto R, Tsuchiya K, Watanabe M: IL-7 Is essential for the development and the persistence of chronic colitis. J Immunol. 2007, 178: 4737-4748.
Nemoto Y, Kanai T, Makita S, Okamoto R, Totsuka T, Takeda K, Watanabe M: Bone marrow retaining colitogenic CD4+ T cells may be a pathogenic reservoir for chronic colitis. Gastroenterology. 2007, 132: 176-189. 10.1053/j.gastro.2006.10.035.
Fry TJ, Mackall CL: The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance. J Immunol. 2005, 174: 6571-6576.
Fry TJ, Mackall CL: Interleukin-7: from bench to clinic. Blood. 2002, 99: 3892-3904. 10.1182/blood.V99.11.3892.
Vivien L, Benoist C, Mathis D: T lymphocytes need IL-7 but not IL-4 or IL-6 to survive in vivo. Int Immunol. 2001, 13: 763-768. 10.1093/intimm/13.6.763.
Shinohara T, Nemoto Y, Kanai T, Kameyama K, Okamoto R, Tsuchiya K, Nakamura T, Totsuka T, Ikuta K, Watanabe M: Upregulated IL-7 receptor (alpha) expression on colitogenic memory CD4+ T cells may participate in the development and persistence of chronic colitis. J Immunol. 2011, 186: 2623-2632. 10.4049/jimmunol.1000057.
Coombes JL, Powrie F: Dendritic cells in intestinal immune regulation. Nat Rev Immunol. 2008, 8: 435-446. 10.1038/nri2335.
Guimond M, Veenstra RG, Grindler DJ, Zhang H, Cui Y, Murphy RD, Kim SY, Na R, Hennighausen L, Kurtulus S: Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nat Immunol. 2009, 10: 149-157.
Fort MM, Leach MW, Rennick DM: A role for NK cells as regulators of CD4+ T cells in a transfer model of colitis. J Immunol. 1998, 161: 3256-3261.
Laroux FS, Norris HH, Houghton J, Pavlick KP, Bharwani S, Merrill DM, Fuseler J, Chervenak R, Grisham MB: Regulation of chronic colitis in athymic nu/nu (nude) mice. Int Immunol. 2004, 16: 77-89. 10.1093/intimm/dxh006.
van Roon JA, Verweij MC, Wijk MW, Jacobs KM, Bijlsma JW, Lafeber FP: Increased intraarticular interleukin-7 in rheumatoid arthritis patients stimulates cell contact-dependent activation of CD4(+) T cells and macrophages. Arthritis Rheum. 2005, 52: 1700-1710. 10.1002/art.21045.
Ohana M, Okazaki K, Oshima C, Andra's D, Nishi T, Uchida K, Uose S, Nakase H, Matsushima Y, Chiba T: A critical role for IL-7R signaling in the development of Helicobacter felis-induced gastritis in mice. Gastroenterology. 2001, 121: 329-336. 10.1053/gast.2001.26289.