Cyclooxygenase-2 blockade inhibits accumulation and function of myeloid-derived suppressor cells and restores T cell response after traumatic stress

Abstract

Myeloid-derived suppressor cells (MDSCs) play a crucial role in T cell dysfunction, which is related to poor outcome in patients with severe trauma. Cyclooxygenase-2 (Cox-2) contributes to immune disorder in trauma and infection via production of prostaglandin E2. However, the role of Cox-2 in the accumulation and function of MDSCs after traumatic stress has not been fully elucidated. In the present study, we treated murine trauma model with NS398, a selective Cox-2 inhibitor. Then the percentages of CD11b+/Gr-1+ cells, proliferation and apoptosis of CD4+ T cells were determined. Arginase activity and arginase-1 (Arg-1) protein expression of splenic CD11b+/Gr-1+ cells, and delayed-type hypersensitivity (DTH) response were analyzed. The results showed that Cox-2 blockade significantly decreased the percentages of CD11b+/Gr-1+ cells in the spleen and bone marrow 48 and 72 h after traumatic stress. NS398 inhibited arginase activity and down-regulated the Arg-1 expression of splenic CD11b+/Gr-1+ cells. Moreover, NS398 could promote proliferation and inhibit apoptosis of CD4+ T cells. It also restored DTH response of traumatic mice. Taken together, our data revealed that Cox-2 might play a pivotal role in the accumulation and function of MDSC after traumatic stress.

Keywords

myeloid-derived suppressor cells / trauma / T cell dysfunction / cyclooxygenase-2

References

[1] MartinGS, ManninoDM, EatonS, et al.. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med, 2003, 348(16): 1546-1554

[2] WebsterNR, GalleyHF. Immunomodulation in the critically ill. Br J Anaesth, 2009, 103(1): 70-81

[3] HotchkissRS, MonneretG, PayenD. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis, 2013, 13(3): 260-268

[4] SauaiaA, MooreFA, MooreEE, et al.. Epidemiology of trauma deaths: a reassessment. J Trauma, 1995, 38(2): 185-193

[5] GabrilovichDI, BronteV, ChenSH, et al.. The terminology issue for myeloid-derived suppressor cells. Cancer Res, 2007, 67(1): 425

[6] GabrilovichDI, NagarajS. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol, 2009, 9(3): 162-174

[7] OchoaAC, ZeaAH, HernandezC, et al.. Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin Cancer Res, 2007, 13(2pt2): 721s-726s

[8] SrivastavaMK, SinhaP, ClementsVK, et al.. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res, 2010, 70(1): 68-77

[9] SinhaP, ClementsVK, FultonAM, et al.. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res, 2007, 67(9): 4507-4513

[10] LiW, WuK, ZhaoE, et al.. HMGB1 recruits myeloid derived suppressor cells to promote peritoneal dissemination of colon cancer after resection. Biochem Biophys Res Commun, 2013, 436(2): 156-161

[11] ChandraD, JahangirA, Quispe-TintayaW, et al.. Myeloid-derived suppressor cells have a central role in attenuated Listeria monocytogenes-based immunotherapy against metastatic breast cancer in young and old mice. Br J Cancer, 2013, 108(11): 2281-2290

[12] FujiiW, AshiharaE, HiraiH, et al.. Myeloid-derived suppressor cells play crucial roles in the regulation of mouse collagen-induced arthritis. J Immunol, 2013, 191(3): 1073-1081

[13] RyanSO, JohnsonJL, CobbBA. Neutrophils confer T cell resistance to myeloid-derived suppressor cell-mediated suppression to promote chronic inflammation. J Immunol, 2013, 190(10): 5037-5047

[14] DelanoMJ, ScumpiaPO, WeinsteinJS, et al.. MyD88-dependent expansion of an immature GR-1+ CD11b+ population induces T cell suppression and Th2 polarization in sepsis. J Exp Med, 2007, 204(6): 1463-1474

[15] MuneraV, PopovicPJ, BrykJ, et al.. Stat 6-dependent induction of myeloid derived suppressor cells after physical injury regulates nitric oxide response to endotoxin. Ann Surg, 2010, 251(1): 120-126

[16] SanderLE, SackettSD, DierssenU, et al.. Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function. J Exp Med, 2010, 207(7): 1453-1464

[17] RenD, BiQ, LiL, et al.. Myeloid-derived suppressor cells accumulate in the liver site after sepsis to induce immunosuppression. Cell Immunol, 2012, 279(1): 12-20

[18] MakarenkovaVP, BansalV, MattaBM, et al.. CD11b+/Gr-1+ myeloid suppressor cells cause T cell dysfunction after traumatic stress. J Immunol, 2006, 176(4): 2085-2094

[19] BrykJA, PopovicPJ, ZenatiMS, et al.. Nature of myeloid cells expressing arginase 1 in peripheral blood after trauma. J Trauma, 2010, 68(4): 843-852

[20] ZhangK, BaiX, LiR, et al.. Endogenous glucocorticoids promote the expansion of myeloid-derived suppressor cells in a murine model of trauma. Int J Mol Med, 2012, 30(2): 277-282

[21] WangD, DuboisRN. Eicosanoids and cancer. Nat Rev Cancer, 2010, 10(3): 181-193

[22] RodriguezPC, HernandezCP, QuicenoD, et al.. Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J Exp Med, 2005, 202(7): 931-939

[23] MaoY, PoschkeI, WennerbergE, et al.. Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms. Cancer Res, 2013, 73(13): 3877-3887

[24] FujitaM, KohanbashG, Fellows-MayleW, et al.. COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells. Cancer Res, 2011, 71(7): 2664-2674

[25] LiongEC, XiaoJ, LauTY, et al.. Cyclooxygenase inhibitors protect D-galactosamine/lipopolysaccharide induced acute hepatic injury in experimental mice model. Food Chem Toxicol, 2012, 50(3–4): 861-866

[26] LiB, LiYM, LiX, et al.. COX-2 inhibition improves immune system homeostasis and decreases liver damage in septic rats. J Surg Res, 2009, 157(1): 43-47

[27] BruegelM, LudwigU, KleinhempelA, et al.. Sepsis-associated changes of the arachidonic acid metabolism and their diagnostic potential in septic patients. Crit Care Med, 2012, 40(5): 1478-1486

[28] SadikotRT, ZengH, AzimAC, et al.. Bacterial clearance of Pseudomonas aeruginosa is enhanced by the inhibition of COX-2. Eur J Immunol, 2007, 37(4): 1001-1009

[29] GoldmannO, HertzénE, HechtA, et al.. Inducible cyclooxygenase released prostaglandin E2 modulates the severity of infection caused by Streptococcus pyogenes. J Immunol, 2010, 185(4): 2372-2381

[30] NascimentoDC, Alves-FilhoJC, SonegoF, et al.. Role of regulatory T cells in long-term immune dysfunction associated with severe sepsis. Crit Care Med, 2010, 38(8): 1718-1725

[31] HotchkissRS. Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med, 2003, 348(2): 138-150

[32] MaJ, ZhaoX, SuQ, et al.. Effect of early intensive insulin therapy on immune function of aged patients with severe trauma. J Huazhong Univ Sci Technolog Med Sci, 2012, 32(3): 400-404

[33] ObermajerN, MuthuswamyR, LesnockJ, et al.. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood, 2011, 118(20): 5498-5505

[34] DeriveM, BouazzaY, AlauzetC, et al.. Myeloid-derived suppressor cells control microbial sepsis. Intensive Care Med, 2012, 38(6): 1040-1049

[35] CuencaAG, DelanoMJ, Kelly-ScumpiaKM, et al.. A paradoxical role for myeloid-derived suppressor cells in sepsis and trauma. Mol Med, 2011, 17(3–4): 281-292

[36] BrudeckiL, FergusonDA, McCallCE, et al.. Myeloid-derived suppressor cells evolve during sepsis and can enhance or attenuate the systemic inflammatory response. Infect Immun, 2012, 80(6): 2026-2034

[37] FredenburghLE, VelandiaMM, MaJ, et al.. Cyclooxygenase-2 deficiency leads to intestinal barrier dysfunction and increased mortality during polymicrobial sepsis. J Immunol, 2011, 187(10): 5255-5267