The protective role of myeloid-derived suppressor cells in concanavalin A-induced hepatic injury

Abstract

The mechanism underlying T cell-mediated fulminant hepatitis is not fully understood. In this study, we investigated whether myeloid derived suppressor cells (MDSCs) could prevent the concanavalin A (ConA)- induced hepatitis through suppressing T cell proliferation. We observed an increase in the frequencies of MDSCs in mouse spleen and liver at early stage of ConA treatment, implicating that the MDSCs might be involved in the initial resistance of mice against ConAmediated inflammation. Subpopulation analysis showed that the MDSCs in liver of ConA-induced mice were mainly granulocytic MDSCs. Adoptive transfer of the bone marrow-derived MDSCs into ConA-treated mice showed that the MDSCs migrated into the liver and spleen where they suppressed T cell proliferation through ROS pathway. In addition, the frequencies of MDSCs in mice were also significantly increased by the treatment with immune suppressor glucocorticoids. Transfer of MDSCs into the regulatory T cell (Treg)- depleted mice showed that the protective effect of MDSCs on ConA-induced hepatitis is Treg-independent. In conclusion, our results demonstrate that MDSCs possess a direct protective role in T cell-mediated hepatitis, and increasing the frequency of MDSCs by either adoptive transfer or glucocorticoid treatment represents a potential cell-based therapeutic strategy for the acute inflammatory disease.

Keywords

myeloid derived suppressor cells / T cellmediated hepatitis / ROS / glucocorticoids / concanavalin A (ConA) / adoptive transfer / glucocorticoid treatment

References

[1] Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI (2001) Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol166: 678-689

[2] Barnes PJ, Adcock IM (2009) Glucocorticoid resistance in inflammatory diseases. Lancet373: 1905-1917

[3] Bronte V, Zanovello P (2005) Regulation of immune responses by Larginine metabolism. Nat Rev Immunol5: 641-654

[4] Cai W, Qin A, Guo P, Yan D, Hu F, Yang Q, Xu M, Fu Y, Zhou J, Tang X (2013) Clinical signiflcance and functional studies of myeloidderived suppressor cells in chronic hepatitis C patients. J Clin Immunol33: 798-808

[5] Chang KM (2003) Immunopathogenesis of hepatitis C virus infection. Clin Liver Dis7: 89-105

[6] Chen S, Akbar SM, Abe M, Hiasa Y, Onji M (2011) Immunosuppressive functions of hepatic myeloid-derived suppressor cells of normal mice and in a murine model of chronic hepatitis B virus. Clin Exp Immunol166: 134-142

[7] Cheng SE, Lee IT, Lin CC, Wu WL, Hsiao LD, Yang CM (2013) ATP mediates NADPH oxidase/ROS generation and COX-2/PGE2 expression in A549 cells: role of P2 receptor-dependent STAT3 activation. PLoS One8: e54125

[8] Chou HS, Hsieh CC, Yang HR, Wang L, Arakawa Y, Brown K, Wu Q, Lin F, Peters M, Fung JJ (2011) Hepatic stellate cells regulate immune response by way of induction of myeloid suppressor cells in mice. Hepatology53: 1007-1019

[9] Cripps JG, Gorham JD (2011) MDSC in autoimmunity. Int Immunopharmacol11: 789-793

[10] Czaja AJ, Davis GL, Ludwig J, Taswell HF (1984) Complete resolution of inflammatory activity following corticosteroid treatment of Hbsag-negative chronic active hepatitis. Hepatology4: 622-627

[11] Ducci H, Katz R (1952) Cortisone, Acth and antibiotics in fulminant hepatitis. Gastroenterology21: 357-374

[12] Elenkov IJ, Chrousos GP (1999) Stress hormones, Th1/Th2 patterns, Pro/Anti-inflammatory cytokines and susceptibility to disease. Trends Endocrinol Metab10: 359-368

[13] Erhardt A, Biburger M, Papadopoulos T, Tiegs G (2007) IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice. Hepatology45: 475-485

[14] Franchimont D, Galon J, Gadina M, Visconti R, Zhou Y, Aringer M, Frucht DM, Chrousos GP, O’Shea JJ (2000) Inhibition of Th1 immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat4 phosphorylation in T lymphocytes. J Immunol164: 1768-1774

[15] Fujiwara K, Yasui S, Okitsu K, Yonemitsu Y, Oda S, Yokosuka O (2010) The requirement for a sufflcient period of corticosteroid treatment in combination with nucleoside analogue for severe acute exacerbation of chronic hepatitis B. J Gastroenterol45: 1255-1262

[16] Gabrilovich D (2004) Mechanisms and functional signiflcance of tumour-induced dendritic-cell defects. Nat Rev Immunol4: 941-952

[17] Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol9: 162-174

[18] Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol12: 253-268

[19] Garcia MR, Ledgerwood L, Yang Y, Xu J, Lal G, Burrell B, Ma G, Hashimoto D, Li Y, Boros P (2010) Monocytic suppressive cells mediate cardiovascular transplantation tolerance in mice. J Clin Invest120: 2486-2496

[20] Greten TF, Manns MP, Korangy F (2011) Myeloid derived suppressor cells in human diseases. Int Immunopharmacol11: 802-807

[21] Haverkamp JM, Crist SA, Elzey BD, Cimen C, Ratliff TL (2011) In vivo suppressive function of myeloid-derived suppressor cells is limited to the inflammatory site. Eur J Immunol41: 749-759

[22] Hegde VL, Nagarkatti PS, Nagarkatti M (2011) Role of myeloidderived suppressor cells in amelioration of experimental autoimmune hepatitis following activation of TRPV1 receptors by cannabidiol. PLoS One6: e18281

[23] Hines IN, Kremer M, Isayama F, Perry AW, Milton RJ, Black AL, Byrd CL, Wheeler MD (2007) Impaired liver regeneration and increased oval cell numbers following T cell-mediated hepatitis. Hepatology46: 229-241

[24] Hong F, Jaruga B, Kim WH, Radaeva S, El-Assal ON, Tian Z, Nguyen VA, Gao B (2002) Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS. J Clin Invest110: 1503-1513

[25] Ilkovitch D, Lopez DM (2009) The liver is a site for tumor-induced myeloid-derived suppressor cell accumulation and immunosuppression. Cancer Res69: 5514-5521

[26] Jaruga B, Hong F, Sun R, Radaeva S, Gao B (2003) Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: Up-regulating eotaxins and IL-5 and recruiting leukocytes. J Immunol171: 3233-3244

[27] Lafdil F, Wang H, Park O, Zhang W, Moritoki Y, Yin S, Fu XY, Gershwin ME, Lian ZX, Gao B (2009) Myeloid STAT3 inhibits T cell-mediated hepatitis by regulating T helper 1 cytokine and interleukin-17 production. Gastroenterology137(2125-2135): e2121-e2122

[28] Lee RWJ, Creed TJ, Schewitz LP, Newcomb PV, Nicholson LB, Dick AD, Dayan CM (2007) CD4(+)CD25(int) T cells in inflammatory diseases refractory to treatment with Glucocorticoids. J Immunol179: 7941-7948

[29] Li HQ, Han YM, Guo QL, Zhang MG, Cao XT (2009) Cancerexpanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J Immunol182: 240-249

[30] Nagaraj S, Gupta K, Pisarev V, Kinarsky L, Sherman S, Kang L, Herber DL, Schneck J, Gabrilovich DI (2007) Altered recognition of antigen is a mechanism of CD8+ Tcell tolerance in cancer. Nat Med13: 828-835

[31] Pan PY, Wang GX, Yin B, Ozao J, Ku T, Divino CM, Chen SH (2008) Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function. Blood111: 219-228

[32] Radaeva S, Sun R, Pan HN, Hong F, Gao B (2004) Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology39: 1332-1342

[33] Rehermann B (2000) Intrahepatic T cells in hepatitis B: viral control versus liver cell injury. J Exp Med191: 1263-1268

[34] Richman LK, Klingenstein RJ, Richman JA, Strober W, Berzofsky JA (1979) Murine Kupffer cell. 1. Characterization of the cell serving accessory function in antigen-speciflc T-cell proliferation. J Immunol123: 2602-2609

[35] Rodriguez PC, Quiceno DG, Ochoa AC (2007) L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood109: 1568-1573

[36] Rosen HR, Miner C, Sasaki AW, Lewinsohn DM, Conrad AJ, Bakke A, Bouwer HGA, Hinrichs DJ (2002) Frequencies of HCV-speciflc effector CD4+T cells by flow cytometry: correlation with clinical disease stages. Hepatology35: 190-198

[37] Schleimer RP, Kato A, Peters A, Conley D, Kim J, Liu MC, Harris KE, Kuperman DA, Chandra R, Favoreto S Jr (2009) Epithelium, inflammation, and immunity in the upper airways of humans: studies in chronic rhinosinusitis. Proc Am Thorac Soc6: 288-294

[38] Suda T, Chida K, Matsuda H, Hashizume H, Ide K, Yokomura K, Suzuki K, Kuwata H, Miwa S, Nakano H (2003) High-dose intravenous glucocorticoid therapy abrogates circulating dendritic cells. J Allergy Clin Immunol112: 1237-1239

[39] Tacke RS, Lee HC, Goh C, Courtney J, Polyak SJ, Rosen HR, Hahn YS (2012) Myeloid suppressor cells induced by hepatitis C virus suppress T-cell responses through the production of reactive oxygen species. Hepatology55: 343-353

[40] Takahashi K, Murakami M, Kikuchi H, Oshima Y, Kubohara Y (2011) Derivatives of Dictyostelium differentiation-inducing factors promote mitogen-activated IL-2 production via AP-1 in Jurkat cells. Life Sci88: 480-485

[41] Tiegs G (2007) Cellular and cytokine-mediated mechanisms of inflammation and its modulation in immune-mediated liver injury. Z Gastroenterol45: 63-70

[42] Varga G, Ehrchen J, Tsianakas A, Tenbrock K, Rattenholl A, Seeliger S, Mack M, Roth J, Sunderkoetter C (2008) Glucocorticoids induce an activated, anti-inflammatory monocyte subset in mice that resembles myeloid-derived suppressor cells. J Leukoc Biol84: 644-650

[43] Wolf D, Hallmann R, Sass G, Sixt M, Kusters S, Fregien B, Trautwein C, Tiegs G (2001) TNF-alpha-induced expression of adhesion molecules in the liver is under the control of TNFR1— relevance for concanavalin A-induced hepatitis. J Immunol166: 1300-1307

[44] Xia S, Sha H, Yang L, Ji Y, Ostrand-Rosenberg S, Qi L (2011) Gr-1+ CD11b+ myeloid-derived suppressor cells suppress inflammation and promote insulin sensitivity in obesity. J Biol Chem286: 23591-23599

[45] Yin B, Ma G, Yen CY, Zhou Z, Wang GX, Divino CM, Casares S, Chen SH, Yang WC, Pan PY (2010) Myeloid-derived suppressor cells prevent type 1 diabetes in murine models. J Immunol185: 5828-5834

[46] Yu S, Fang Y, Sharp GC, Braley-Mullen H (2010) Transgenic expression of TGF-beta on thyrocytes inhibits development of spontaneous autoimmune thyroiditis and increases regulatory T cells in thyroids of NOD.H-2h4 mice. J Immunol184: 5352-5359

[47] Zhang J, Wang B, Zhang W, Wei Y, Bian Z, Zhang CY, Li L, Zen K (2013) Protein tyrosine phosphatase 1B deflciency ameliorates murine experimental colitis via the expansion of myeloid-derived suppressor cells. PLoS One8: e70828

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2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.