Myeloid-derived suppressor cells in secondary sepsis: Is there an association with lethal outcome?

Ivo  Udovičić; Maja Šurbatović; Goran  Rondović; Ivan  Stanojević; Snježana  Zeba; Dragan Djordjević; Ana  Popadić; Snežana  Milosavljević; Nikola Stanković; Džihan  Abazović; Danilo  Vojvodić

doi:10.2298/VSP180706133U

Ivo Udovičić Military Medical Academy, Clinic of Anesthesiology and Intensive Therapy, Belgrade, Serbia
Maja Šurbatović Military Medical Academy, Clinic of Anesthesiology and Intensive Therapy, Belgrade, Serbia
Goran Rondović Military Medical Academy, Clinic of Anesthesiology and Intensive Therapy, Belgrade, Serbia
Ivan Stanojević University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia
Snježana Zeba Military Medical Academy, Clinic of Anesthesiology and Intensive Therapy, Belgrade, Serbia
Dragan Djordjević Military Medical Academy, Clinic of Anesthesiology and Intensive Therapy, Bel gra de, Serbia
Ana Popadić Military Medical Academy, Clinic of Anesthesiology and Intensive Therapy, Belgrade, Serbia
Snežana Milosavljević Clinical Hospital Center Kosovska Mitrovica, Department of Anesthesiology, Kosovska Mitrovica, Serbia
Nikola Stanković Mother And Child Health Care Institute of Serbia „ Dr. Vukan Čupić“, Department of Anesthesiology and Intensive Therapy, Belgrade, Serbia
Džihan Abazović Emergency Medical Centar of Montenegro, Podgorica, Montenegro
Danilo Vojvodić University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia

DOI: https://doi.org/10.2298/VSP180706133U

Keywords: myeloid cells, myeloid-derived suppressor cells, mortality, prognosis, sepsis, treatment outcome

Abstract

Background/Aim. Role of myeloid-derived suppressor cells (MDSCs) in human host response to sepsis still needs to be clarified. The aim of our study was to determine whether frequency and/or absolute numbers of the MDSCs were associated with outcome in critically ill patients with secondary sepsis and/or septic shock. Methods. Total of 40 critically ill patients with secondary sepsis were enrolled in a prospective study. We detected and enumerated both main subsets of MDSCs: granulocytic (G)-MDSCs and monocytic (M)-MDSCs on the Day 1 (the day of hospital admission) and the Day 5 after the. The primary end-point was hospital mortality. Results. Increased frequencies and absolute numbers of subpopulations corresponding to MDSCs were associated with poor outcome. As far as relative kinetics was concerned, in both survivors and non-survivors, sepsis duration from 1th to 5th day was accompanied by an increase in MDSCs values of both investigated subpopulations. In contrast to findings of stepwise multivariate logistic regression analysis of the variables on the Day 1, on the Day 5 it was determined that the Sequential Organ Failure Assessment (SOFA) score (OR 2.350; p < 0.05) and G-MDSCs frequencies (OR 3.575; p < 0.05) were independent predictors of lethal outcome. Conclusion. These findings suggest harmful role of MDSCs in secondary sepsis.

Author Biography

Ivo Udovičić, Military Medical Academy, Clinic of Anesthesiology and Intensive Therapy, Belgrade, Serbia

Odsek za lečenje kritično obolelih i povređenih pacijenata, anesteziolog

References

Young MR, Newby M, Wepsic HT. Hematopoiesis and suppres-sor bone marrow cells in mice bearing large metastatic Lewis lung carcinoma tumors. Cancer Res 1987; 47(1): 100–5.

Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009; 9(3): 162–74.

Nagaraj S, Collazo M, Corzo CA, Youn JI, Ortiz M, Quiceno D, et al. Regulatory myeloid suppressor cells in health and disease. Cancer Res 2009; 69(19): 7503–6.

Cuenca AG, Delano MJ, Kelly-Scumpia KM, Moreno C, Scumpia PO, Laface DM, et al. A paradoxical role for myeloid-derived sup¬pressor cells in sepsis and trauma. Mol Med 2011; 17(3-4): 281–92.

Delano MJ, Scumpia PO, Weinstein JS, Coco D, Nagaraj S, Kelly-Scum¬pia KM,et al. MyD88-dependent expansion of an imma-ture GR-1(+)CD11b(+) population induces T cell suppres-sion and Th2 polarization in sepsis. J Exp Med 2007; 204(6): 1463–74.

Delano MJ, Thayer T, Gabrilovich S, Kelly-Scumpia KM, Winfield RD, Scumpia PO,et al. Sepsis induces early alterations in innate immunity that impact mortality to secondary infection. J Im-munol 2011; 186(1): 195–202.

Shankar-Hari M, Deutschman CS, Singer M. Do we need a new definition of sepsis? Intensive Care Med 2015; 41(5): 909–11.

Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, An-nane D, Bauer M, et al. The Third International Consensus Defini¬tions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315(8): 801–10.

Gentile LF, Cuenca AG, Efron PA, Ang D, Bihorac A, McKinley BA, et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg 2012; 72(6): 1491–501.

Surbatovic M, Veljovic M, Jevdjic J, Popovic N, Djordjevic D, Rada-kovic S. Immunoinflammatory response in critically ill pa¬tients: severe sepsis and/or trauma. Mediators Inflamm 2013; 2013: 362793.

Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immuno-sup¬pression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 2013; 13(12): 862–74.

Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sep-sis: a novel understanding of the disorder and a new therapeu-tic approach. Lancet Infect Dis 2013; 13(3): 260–8.

Ray A, Chakraborty K, Ray P. Immunosuppressive MDSCs in-duced by TLR signaling during infection and role in resolution of inflammation. Front Cell Infect Microbiol 2013; 3: 52.

Hotchkiss RS, Moldawer LL. Parallels between cancer and in-fec¬tious disease. N Engl J Med 2014; 371(4): 380–3.

Lai D, Qin C, Shu Q. Myeloid-derived suppressor cells in sep-sis. Biomed Res Int 2014; 2014: 598654.

Derive M, Bouazza Y, Alauzet C, Gibot S. Myeloid-derived sup-pressor cells control microbial sepsis. Intensive Care Med 2012; 38(6): 1040–9.

Brudecki L, Ferguson DA, McCall CE, El Gazzar M. Myeloid-de¬rived suppressor cells evolve during sepsis and can enhance or attenuate the systemic inflammatory response. Infect Im-mun 2012; 80(6): 2026–34.

Moreno R, Vincent JL, Matos R, Mendonça A, Cantraine F, Thijs L, et al. The use of maximum SOFA score to quantify organ dys¬function/failure in intensive care. Results of a prospective, multicentre study. Working Group on Sepsis related Problems of the ESICM. Intensive Care Med 1999; 25(7): 686–96.

Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physi¬ology Score (SAPS II) based on a European/North American multicenter study. JAMA 1993; 270(24): 2957–63.

Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med 1985; 13(10): 818–29.

Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Fer-rer R, et al. Surviving Sepsis Campaign: International Guide-lines for Management of Sepsis and Septic Shock: 2016. In-tensive Care Med 2017; 43(3): 304–77.

Sander LE, Sackett SD, Dierssen U, Beraza N, Linke RP, Müller M, et al. Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived sup-pressor cell function. J Exp Med 2010; 207(7): 1453–64.

Stanojevic I, Miller K, Kandolf-Sekulovic L, Mijuskovic Z, Zolotarev-ski L, Jovic M, et al. A subpopulation that may correspond to granulocytic myeloid-derived suppressor cells reflects the clini-cal stage and progression of cutaneous melanoma. Int Immu-nol 2016; 28(2): 87–97.

Sagiv JY, Michaeli J, Assi S, Mishalian I, Kisos H, Levy L, et al. Phe¬notypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep 2015; 10(4): 562–74.

Jordan KR, Amaria RN, Ramirez O, Callihan EB, Gao D, Bora-kove M, et al. Myeloid-derived suppressor cells are associated with disease progression and decreased overall survival in ad-vanced-stage melanoma patients. Cancer Immunol Immuno-ther 2013; 62(11): 1711–22.

Schmielau J, Finn OJ. Activated granulocytes and granulocyte-de¬rived hydrogen peroxide are the underlying mechanism of suppression of T-cell function in advanced cancer patients. Cancer Res 2001; 61(12): 4756–60.

Rodriguez PC, Ernstoff MS, Hernandez C, Atkins M, Zabaleta J, Si¬erra R, et al. Arginase I-producing myeloid-derived suppres-sor cells in renal cell carcinoma are a subpopulation of activat-ed granulocytes. Cancer Res 2009; 69(4): 1553–60.

Darcy CJ, Minigo G, Piera KA, Davis JS, McNeil YR, Chen Y, et al. Neutrophils with myeloid derived suppressor function de-plete arginine and constrain T cell function in septic shock pa-tients. Crit Care 2014; 18(4): R163.

Surbatovic M, Radakovic S. Tumor necrosis factor-α levels early in severe acute pancreatitis: is there predictive value regarding severity and outcome? J Clin Gastroenterol 2013; 47(7): 637–43.

Djordjevic D, Pejovic J, Surbatovic M, Jevdjic J, Radakovic S, Veljovic M, et al. Prognostic value and daily trend of interleukin-6, neutrophil CD64 expression, C-reactive protein and lipopoly-saccharide-binding protein in critically ill patients: reliable pre-dictors of outcome or not? J Med Biochem 2015; 34(4): 431–9.

Youn JI, Gabrilovich DI. The biology of myeloid-derived sup-pres¬sor cells: the blessing and the curse of morphological and functional heterogeneity. Eur J Immunol 2010; 40(11): 2969–75.

Rodrigues JC, Gonzalez GC, Zhang L, Ibrahim G, Kelly JJ, Gus-tafson MP, et al. Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties. Neuro Oncol. 2010;12(4):351–65.

Mathias B, Delmas AL, Ozrazgat-Baslanti T, Vanzant EL, Szpila BE, Mohr AM, et al. Human myeloid-derived suppressor cells are associated with chronic immune suppression after severe sepsis/septic shock. Ann Surg 2017; 265(4): 827–34.

Uhel F, Azzaoui I, Grégoire M, Pangault C, Dulong J, Tadié JM, et al. Early expansion of circulating granulocytic myeloid-derived suppressor cells predicts development of nosocomial infec-tions in patients with sepsis. Am J Respir Crit Care Med 2017; 196(3): 315–27.

Cuenca AG, Moldawer LL. Myeloid-derived suppressor cells in sepsis: friend or foe? Intensive Care Med 2012; 38(6): 928–30.

Zhu X, Pribis JP, Rodriguez PC, Morris SM Jr, Vodovotz Y, Billiar TR, et al. The central role of arginine catabolism in T-cell dys-function and increased susceptibility to infection after physical injury. Ann Surg 2014; 259(1): 171–8.

Goenka A, Kollmann TR. Development of immunity in early life. J Infect 2015; 71 Suppl 1: S112–20.

Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol 2018; 19(2): 108–19.