Myeloid derived suppressor cells in experimental chronic inflammation
Keywords:
Chronic inflammation, MDSC, flow cytometry, Ehrlich carcinoma, adjuvant arthritisAbstract
Mechanisms of chronic inflammation significantly differ from mechanisms of acute inflammation, which is morphologically characterized by the presence of mast cells, neutrophils and macrophages. In the case of unresolved acute inflammation, by reasons not fully elucidated, a chronic inflammation develops, which is characterized by the presence of T-lymphocytes, macrophages and fibroblasts. Taken together, these cells support prolonged chronic inflammation, a characteristic feature of which is the phenomenon of the simultaneous presence of proinflammatory and anti-inflammatory cytokines. We hypothesized that the key role in this process belongs to so-called myeloid derived suppressor cells (MDSC), which represent a heterogeneous population of early hematopoietic progenitors of myelomonocytic branch (neutrophils and monocytes), and are identified in mice by expression of CD11b and Gr-1 markers and the ability to inhibit NK and cytotoxic T cell activity. We suggested that MDSC phenomenon is not a prerogative of cancer process but most probably is linked to pathogenesis of chronic inflammation, which precedes and to a certain extent induces carcinogenesis.
The aim of the study was a flow cytometric analysis of different MDSC subpopulations (G-MDSC and M-MDSC) in mice with adjuvant arthritis, a classic experimental model of chronic inflammation. Flow cytometry was used as the main method, the applicability of which to the phenotypic evaluation of MDSC was confirmed earlier by Ehrlich carcinoma subcutaneous model in CBA mice. As it turned out, tumor growth correlated with an increase in splenic CD11b+Gr-1+ MDSCs. According to our data, development of local chronic inflammation also resulted in an elevated level of circulating MDSCs. By the end of two weeks after administration of complete Freund's adjuvant (CFA) in the hind limb of CD-1 mice, we showed a more than two-fold increase of total MDSC in the spleen, in both monocyte (M-MDSC) and granulocyte (G-MDSC) MDSC fractions. The increase in MDSCs persisted until forth week. Also, we found a significantly increased level of CD11b+Gr-1+ cells expressing CD184 (CXCR4). In addition, by the end of the fourth week of the chronic inflammation, we observed an increase in MDSCs expressing CD195+ (CCR5+), and an increased proportion of CD62+ MDSC by the second week.
Thus, the processes, associated with the development of local chronic inflammation lead to an increase in the spleen levels of MDSCs and their ability to migrate into the inflammatory sites by increasing the expression of receptors to SDF-1α and RANTES chemoattractants.
References
1 Prasad S., Sung B., Aggarwal B.B. Age-associated chronic diseases require age-old medicine: Role of chronic inflammation // Prev Med.- 2012.- N54.– P.29–37. DOI:10.1016/j.ypmed.2011.11.011
2 Yu B.P., Chung H.Y. The inflammatory process in aging // Rev Clin Gerontol.- 2006.- N16.– P.179–187. DOI: 10.1017/S0959259807002110
3 Lavrovsky Y, Chatterjee B, Clark R.A., Roy A.K. Role of redox-regulated transcription factors in inflammation, aging and age-related diseases // Exp Gerontol.- 2000.- N35.– P.521–532. DOI:10.1016/S0531-5565(00)00118-2
4 Rahman I. Oxidative stress, chromatin remodeling and gene transcription in inflammation and chronic lung diseases // J Biochem Mol Biol.- 2003.- N36.– P.95–109. DIO: 10.5483/BMBRep.2003.36.1.095
5 Aggarwal B.B. Nuclear factor-kB: the enemy within // Cancer Cell.- 2004 - N6.– P.203–208. DIO:10.1016/j.ccr.2004.09.003
6 Roy S., Bagchi D., Raychandhuri S.P. Chronic inflammation Molecular pathophysiology, nutritional and therapeutic interventions. – USA: CRC Press, Talor@Francis Group L.L.C.- 2013.- 472 p.
7 Zeyda M., Farmer D., Todoric J., Aszmann O., Speiser M., Györi G., Zlabinger G.J., Stulnig T.M. Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production // Int J Obes.- 2007.- N31.– P.1420–1428. DIO: 10.1038/sj.ijo.0803632
8 Wolf A.M., Wolf D., Rumpold H., Enrich B., Tilg H. Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes // Biochem Biophys Res Com.- 2004.- N323.– P.630–635. DIO: 10.1016/j.bbrc.2004.08.145
9 Lan H.Y. Diverse roles of TGF-β/Smads in renal fibrosis and Inflammation// Int J Biol Sci.- 2011.- N7.– P.1056-1067.DIO: 10.7150/ijbs.7.1056
10 Han G., Li F., Singh T.P., Wolf P., Wang X.J. The Pro-inflammatory Role of TGFβ1: A Paradox? // Int J Biol S.- 2012.- N8(2).– P.228-235. DIO: 10.7150/ijbs.8.228
11 Gabrilovich D.I., Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system // Nature Rev Immunol.- 2009.- N9.– P.162-174. DIO: 10.1038/nri2506
12 Greten T.F., Manns M.P., Korangy F. Myeloid derived suppressor cells in human diseases // Intern Immunopharm.- 2011.- N11.- P.802–807. DIO: 10.1016/j.intimp.2011.01.003
13 Ostrand-Rosenberg S., Sinha P. Myeloid-derived suppressor cells: Linking inflammation and cancer // J Immunol.- 2009.- N182.- P.4499–4506. DOI: 10.4049/jimmunol.0802740
14 Peranzoni E., Zilio S., Marigo I., Dolcetti L., Zanovello P., Mandruzzato S., Bronte V. Myeloid-derived suppressor cell heterogeneity and subset definition // Curr Opin Immunol.- 2010.- N22.- P.238–244. DIO: 10.1016/j.coi.2010.01.021
15 Obregón-Henao A., Henao-Tamayo M., Orme I.M., Ordway D.J. Gr1intCD11b+ Myeloid-derived suppressor cells in Mycobacterium tuberculosis Infection // PLOS ONE.- 2013.- N8.- Issue 11 e80669. DIO: 10.1371/journal.pone.0080669
16 Chen S., Akbar S.M., Abe M., Hiasa Y., Onji M. Immunosuppressive functions of hepatic myeloid-derived suppressor cells of normal mice and in a murine model of chronic hepatitis B virus // Clin Exp Immunol.- 2011.- N166.- P.134–142. DIO: 10.1111/j.1365-2249.2011.04445.x
17 Xia S.h., Sha H., Yang L., Ji Y., Ostrand-Rosenberg S., Qi L. Gr-1 CD11b Myeloid-derived suppressor cells suppress inflammation and promote insulin sensitivity in obesity // J Biol Chem.- 2011.- N286(26).- P.23591–23599. DIO: 10.1074/jbc.M111.237123
18 Goni O., Alcaide P., Fresno M. Immunosuppression during acute Trypanosoma cruzi infection: involvement of Ly6G (Gr1(+)) CD11b(+) immature myeloid suppressor cells // Int Immunol.- 2002.- N14(10).- P.1125-1131. DIO: 10.1093/intimm/dxf076
19 Mencacci A., Montagnoli C., Bacci A., Cenci E., Pitzurra L., Spreca A., Kopf M., Sharpe A.H., Romani L. CD80+Gr-1+ myeloid cells inhibit development of antifungal Th1 immunity in mice with candidiasis // J Immunol.- 2002.- N169.- P.3180-3189. DIO: 10.4049/jimmunol.169.6.3180
20 European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes // CETS 123. Strasbourg.- 1986.- 11 p.
21 Subiza J.L.,Vinuela J.E., Rodriguez R., Gil J., Figueredo M.A., De la Concha E.G. Development of splenic natural suppressor (NS) cells in Ehrlich tumor-bearing mice // Int J Cancer.- 1989.- N44.- P307-314. DIO: 10.1002/ijc.2910440220
References
1 Prasad S, Sung B, Aggarwal BB (2012) Age-associated chronic diseases require age-old medicine: Role of chronic inflammation, Prev Med, 54: S29–S37. DOI:10.1016/j.ypmed.2011.11.011
2 Yu BP, Chung HY (2006) The inflammatory process in aging, Rev Clin Gerontol, 16:. 179–187. DOI: 10.1017/S0959259807002110
3 Lavrovsky Y, Chatterjee B, Clark RA, Roy AK (2000) Role of redox-regulated transcription factors in inflammation, aging and age-related diseases, Exp Gerontol, 35: 521–532. DOI:10.1016/S0531-5565(00)00118-2
4 Rahman I (2003) Oxidative stress, chromatin remodeling and gene transcription in inflammation and chronic lung diseases,J Biochem Mol Biol, 36: 95–109. DIO: 10.5483/BMBRep.2003.36.1.095
5 Aggarwal BB (2004) Nuclear factor-kB: the enemy within, Cancer Cell, 6: 203–208. DIO:10.1016/j.ccr.2004.09.003
6 Roy S, Bagchi D, Raychandhuri SP (2013) Chronic inflammation Molecular pathophysiology, nutritional and therapeutic interventions, CRC Press, Talor@Francis Group L.L.C., USA. ISBN:978-1-4398-7211-6
7 Zeyda M, Farmer D, Todoric J, Aszmann O, Speiser M, Györi G, Zlabinger GJ, Stulnig TM (2007) Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production,Int J Obes, 31: 1420–1428. DIO: 10.1038/sj.ijo.0803632
8 Wolf AM, Wolf D, Rumpold H, Enrich B, Tilg H (2004) Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes, Biochem Biophys Res Com, 323: 630–635. DIO: 10.1016/j.bbrc.2004.08.145
9 Lan HY (2011) Diverse roles of TGF-β/Smads in renal fibrosis and Inflammation, Int J Biol Sci, 7: 1056-1067.DIO: 10.7150/ijbs.7.1056
10 Han G, Li F, Singh TP, Wolf P, Wang XJ (2012) The Pro-inflammatory Role of TGFβ1: A Paradox?, Int J Biol S, 8(2):228-235. DIO: 10.7150/ijbs.8.228
11 Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system, Nature Rev Immunol, 9:162-174. DIO: 10.1038/nri2506
12 Greten TF, Manns MP, Korangy F (2011) Myeloid derived suppressor cells in human diseases, Intern Immunopharm, 11: 802–807. DIO: 10.1016/j.intimp.2011.01.003
13 Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: Linking inflammation and cancer, J Immunol, 182: 4499–4506. DOI: 10.4049/jimmunol.0802740
14 Peranzoni E, Zilio S, Marigo I, Dolcetti L, Zanovello P, Mandruzzato S, Bronte V (2010) Myeloid-derived suppressor cell heterogeneity and subset definition, Curr Opin Immunol, 22: 238–244. DIO: 10.1016/j.coi.2010.01.021
15 Obregón-Henao A, Henao-Tamayo M, Orme IM, Ordway DJ (2013) Gr1intCD11b+ Myeloid-derived suppressor cells in Mycobacterium tuberculosis Infection, PLOS ONE, 8: Issue 11 e80669. DIO: 10.1371/journal.pone.0080669
16 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 Immunol, 166:134–142. DIO: 10.1111/j.1365-2249.2011.04445.x
17 Xia Sh, 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 Chem, 286 (26): 23591–23599. DIO: 10.1074/jbc.M111.237123
18 Goni O, Alcaide P, Fresno M (2002) Immunosuppression during acute Trypanosoma cruzi infection: involvement of Ly6G (Gr1(+)) CD11b(+) immature myeloid suppressor cells, Int Immunol, 14(10):1125-1131. DIO: 10.1093/intimm/dxf076
19 Mencacci A, Montagnoli C, Bacci A, Cenci E, Pitzurra L, Spreca A, Kopf M, Sharpe AH, Romani L (2002) CD80+Gr-1+ myeloid cells inhibit development of antifungal Th1 immunity in mice with candidiasis, J Immunol, 169: 3180-3189. DIO: 10.4049/jimmunol.169.6.3180
20 European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes (1986) European Treaty Series – No: 123, Strasbourg.
21 Subiza JL,Vinuela JE, Rodriguez R, Gil J, Figueredo MA, De la Concha EG (1989) Development of splenic natural suppressor (NS) cells in Ehrlich tumor-bearing mice, Int J Cancer, 44:307-314. DIO: 10.1002/ijc.2910440220
