髓源性抑制细胞在脓毒症中的研究进展

doi:10.3877/cma.j.issn.2096-1537.2024.03.011

脓毒症是收住ICU的主要原因，从脓毒症定义来看，脓毒症始发于感染，发展于机体的免疫反应失调，恶化在组织和器官。脓毒症的发病机制复杂，多种机制参与其病理生理过程，机体的免疫状态严重失衡。随着ICU医师对脓毒症的不断认识及医疗技术的快速提升，脓毒症患者一般能度过早期的炎症风暴，而后期因免疫抑制导致二次感染，从而增加了病死率。目前针对脓毒症的研究主要集中在免疫抑制及寻找免疫调节治疗两个方面。本文就近年来髓源性抑制细胞（MDSC）的命名、来源以及在脓毒症免疫中的研究进展进行综述，为脓毒症免疫失调寻找潜在的治疗方法提供重要的理论基础。

关键词: 脓毒症, 髓源性抑制细胞, 分化, 高原地区

Sepsis is the main cause of ICU admission. Sepsis originates from an infection and progresses due to host desregulated immune response, ultimately leading to deterioration in tissues and organs. The pathogenesis of sepsis is complicate, with multiple mechanisms involved in its pathological and physiological processes. The immune state of the body is significantly disrupted. Thanks to the ongoing advancements in medical technology and the increasing knowledge of sepsis by ICU physicians, sepsis patients can typically endure the initial inflammatory response. However, in the later stages, they are susceptible to secondary infections due to immune suppression, which still carries a significant risk of mortality. At present, the research on sepsis mainly focuses on immunosuppression and immunomodulatory strategies. We review the nomenclature, origin, and research progress of myeloid suppressor cells (MDSCs) in sepsis in this manuscript. It also presents the theoretical foundation for future treatments of sepsis-related immune dysfunctions.

Key words: Sepsis, Medullary suppressor cells, Differentiation, Plateau area

图1 MDSC分化注：MDSC为髓源性抑制细胞；STAT3/JAK为信号转导与转录激活因子3/Janus激酶

图2 脓毒症中MDSC介导免疫抑制的分子机制注：MDSC为髓源性抑制细胞

1	Veglia F, Sanseviero E, Gabrilovich DI. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity [J]. Nat Rev Immunol, 2021, 21(8): 485-498.
2	Krystal G, Sly L, Antignano F, et al. Re: the terminology issue for myeloid-derived suppressor cells [J]. Cancer Res, 2007, 67(8): 3986.
3	Schrijver IT, Théroude C, Roger T. Myeloid-derived suppressor cells in sepsis [J]. Front Immunol, 2019, 10: 327.
4	Barreda DR, Hanington PC, Belosevic M. Regulation of myeloid development and function. by colony stimulating factors [J]. Dev Comp Immunol, 2004, 28(5): 509-554.
5	Almand B, Clark JI, Nikitina E, et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer [J]. J Immunol, 2001, 166(1): 678-689.
6	Luan Y, Mosheir E, Menon MC, et al. Monocytic myeloid-derived suppressor cells accumulate in renal transplant patients and mediate CD4+ Foxp3+ Treg expansion [J]. Am J Transplant, 2013, 13(12): 3123-3131.
7	Condamine T, Dominguez GA, Youn JI, et al. Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients [J]. Sci Immunol, 2016, 1(2): aaf8943.
8	Esher SK, Fidel PL Jr, Noverr MC. Candida/Staphylococcal polymicrobial intra-abdominal infection: pathogenesis and perspectives for a novel form of trained innate immunity [J]. J Fungi (Basel), 2019, 5(2): 37.
9	Condamine T, Mastio J, Gabrilovich DI, Transcriptional regulation of myeloid-derived suppressor cells [J]. J Leukoc Biol, 2015, 98(6): 913-922.
10	Ruan WS, Xu J, Lu YQ. Prospect of using deep learning for predicting differentiation of myeloid progenitor cells after sepsis [J]. Chin Med J (Engl), 2019, 132(15): 1862-1864.
11	Waeckel L, Venet F, Gossez M, et al. Delayed persistence of elevated monocytic MDSC associates with deleterious outcomes in septic shock: a retrospective cohort study [J]. Crit Care, 2020, 24(1): 132.
12	Xu J, Peng Y, Yang M, et al. Increased levels of myeloid-derived suppressor cells in esophageal cancer patients is associated with the complication of sepsis [J]. Biomed Pharmacother, 2020, 125: 109864.
13	Bronte V, Brandau S, Chen SH, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards [J]. Nat Commun, 2016, 7: 12150.
14	Mairhofer DG, Ortner D, Tripp CH, et al. Impaired gp100-specific CD8+T-cell responses in the presence of myeloid-derived suppressor cells in a spontaneous mouse melanoma model [J]. J Invest Dermatol, 2015, 135(11): 2785-2793.
15	Youn JI, Nagaraj S, Collazo M, et al. Subsets of myeloid-derived suppressor cells in tumor-bearing mice [J]. J Immunol, 2008, 181(8): 5791-5802.
16	Ghnewa YG, Fish M, Jennings A, et al. Goodbye SIRS? Innate, trained and adaptive immunity and pathogenesis of organ dysfunction [J]. Med Klin Intensivmed Notfmed, 2020, 115(Suppl 1): 10-14.
17	Rodriguez PC, Ernstoff MS, Hernandez C, et al. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes [J]. Cancer Res, 2009, 69(4): 1553-1560.
18	Yang R, Cai Z, Zhang Y, et al. CD80 in immune suppression by mouse ovarian carcinoma-associated Gr-1+CD11b+ myeloid cells [J]. Cancer Res, 2006, 66(13): 6807-6815.
19	Ochoa AC, Zea AH, Hernandez C, et al. Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma [J]. Clin Cancer Res, 2007, 13(2 Pt 2): 721s-726s.
20	Bronte V, Serafini P, Mazzoni A, et al. L-arginine metabolism in myeloid cells controls T-lymphocyte functions [J]. Trends Immunol, 2003, 24(6): 302-306.
21	Bingisser RM, Tilbrook PA, Holt PG, et al. Macrophage-derived nitric oxide regulates T cell activation via reversible disruption of the JAK3/STAT5 signaling pathway [J]. J Immunol, 1998, 160(12): 5729-5734.
22	Schmielau J, Finn OJ. Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of t-cell function in advanced cancer patients [J]. Cancer Res, 2001, 61(12): 4756-4760.
23	Zea AH, Rodriguez PC, Atkins MB, et al. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion [J]. Cancer Res, 2005, 65(8): 3044-3048.
24	Dolcetti L, Peranzoni E, Ugel S, et al. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF [J]. Eur J Immunol, 2010, 40(1): 22-35.
25	Movahedi K, Guilliams M, Van den Bossche J, et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity [J]. Blood, 2008, 111(8): 4233-4244.
26	Nagaraj S, Gupta K, Pisarev V, et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer [J]. Nat Med, 2007, 13(7): 828-835.
27	Rastad JL, Green WR. Myeloid-derived suppressor cells in murine AIDS inhibit B-cell responses in part via soluble mediators including reactive oxygen and nitrogen species, and TGF-β [J]. Virology, 2016, 499: 9-22.
28	Ohl K, Tenbrock K. Reactive oxygen species as regulators of MDSC-mediated immune suppression [J]. Front Immunol, 2018, 9: 2499.
29	Wang D, DuBois RN. The role of prostaglandin E2 in tumor-associated immunosuppression [J]. Trends Mol Med, 2016, 22(1): 1-3.
30	Krishnamoorthy M, Gerhardt L, Maleki Vareki S. Immunosuppressive effects of myeloid-derived suppressor cells in cancer and immunotherapy [J]. Cells, 2021, 10(5): 1170.
31	Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age [J]. Nat Immunol, 2018, 19(2): 108-119.
32	Hollen MK, Stortz JA, Darden D, et al. Myeloid-derived suppressor cell function and epigenetic expression evolves over time after surgical sepsis [J]. Crit Care, 2019, 23(1): 355.
33	Venet F, Monneret G. Advances in the understanding and treatment of sepsis-induced immunosuppression [J]. Nat Rev Nephrol, 2018, 14(2): 121-137.
34	Janols H, Bergenfelz C, Allaoui R, et al. A high frequency of MDSCs in sepsis patients, with the granulocytic subtype dominating in gram-positive cases [J]. J Leukoc Biol, 2014, 96(5): 685-693.
35	Mathias B, Delmas AL, Ozrazgat-Baslanti T, et al. Human myeloid-derived suppressor cells are associated with chronic immune suppression after severe sepsis/septic shock [J]. Ann Surg, 2017, 265(4): 827-834.
36	Patera AC, Drewry AM, Chang K, et al. Frontline science: defects in immune function in patients with sepsis are associated with PD-1 or expression and can be restored by antibodies targeting PD-1 or PD-L1 [J]. J Leukoc Biol, 2016, 100(6): 1239-1254.
37	Uhel F, Azzaoui I, Grégoire M, et al. Early expansion of circulating granulocytic myeloid-derived suppressor cells predicts development of nosocomial infections in patients with sepsis [J]. Am J Respir Crit Care Med, 2017, 196(3): 315-327.
38	Coudereau R, Waeckel L, Cour M, et al. Emergence of immunosuppressive LOX-1+ PMN-MDSC in septic shock and severe COVID-19 patients with acute respiratory distress syndrome [J]. J Leukoc Biol, 2022, 111(2): 489-496.
39	Darcy CJ, Minigo G, Piera KA, et al. Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients [J]. Crit Care, 2014, 18(4): R163.
40	Guérin E, Orabona M, Raquil MA, et al. Circulating immature granulocytes with T-cell killing functions predict sepsis deterioration [J]. Crit Care Med, 2014, 42(9): 2007-2018.
41	Ruan WS, Feng MX, Xu J, et al. Early activation of myeloid-derived suppressor cells participate in sepsis-induced immune suppression via PD-L1/PD-1 axis [J]. Front Immunol, 2020, 11: 1299.
42	Schrijver IT, Karakike E, Théroude C, et al. High levels of monocytic myeloid-derived suppressor cells are associated with favorable outcome in patients with pneumonia and sepsis with multi-organ failure [J]. Intensive Care Med Exp, 2022, 10(1): 5.
43	De Zuani M, Hortová-Kohoutková M, Andrejčinová I, et al. Human myeloid-derived suppressor cell expansion during sepsis is revealed by unsupervised clustering of flow cytometric data [J]. Eur J Immunol, 2021, 51(7): 1785-1791.
44	Poe SL, Arora M, Oriss TB, et al. STAT1-regulated lung MDSC-like cells produce IL-10 and efferocytose apoptotic neutrophils with relevance in resolution of bacterial pneumonia [J]. Mucosal Immunol, 2013, 6(1): 189-199.
45	Schwarz J, Scheckenbach V, Kugel H, et al. Granulocytic myeloid-derived suppressor cells (GR-MDSC) accumulate in cord blood of preterm infants and remain elevated during the neonatal period [J]. Clin Exp Immunol, 2018, 191(3): 328-337.
46	He YM, Li X, Perego M, et al. Transitory presence of myeloid-derived suppressor cells in neonates is critical for control of inflammation [J]. Nat Med, 2018, 24(2): 224-231.
47	Leiber A, Schwarz J, Köstlin N, et al. Neonatal myeloid derived suppressor cells show reduced apoptosis and immunosuppressive activity upon infection with Escherichia coli [J]. Eur J Immunol, 2017, 47(6): 1009-1021.
48	Niño DF, Sodhi CP, Hackam DJ. Necrotizing enterocolitis: new insights into pathogenesis and mechanisms [J]. Nat Rev Gastroenterol Hepatol, 2016, 13(10): 590-600.
49	Weber R, Umansky V. Fighting infant infections with myeloid-derived suppressor cells [J]. J Clin Invest, 2019, 129(10): 4080-4082.
50	Liu Y, Perego M, Xiao Q, et al. Lactoferrin-induced myeloid-derived suppressor cell therapy attenuates pathologic inflammatory conditions in newborn mice [J]. J Clin Invest, 2019, 129(10): 4261-4275.
51	Diao B, Wang C, Tan Y, et al. Reduction and functional exhaustion of t cells in patients with coronavirus disease 2019 (COVID-19) [J]. Front Immunol, 2020, 11: 827.
52	Falck-Jones S, Vangeti S, Yu M, et al. Functional monocytic myeloid-derived suppressor cells increase in blood but not airways and predict COVID-19 severity [J]. J Clin Invest, 2021, 131(6): e144734.
53	Vanderbeke L, Van Mol P, Van Herck Y, et al. Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity [J]. Nat Commun, 2021, 12(1): 4117.
54	Thompson EA, Cascino K, Ordonez AA, et al. Metabolic programs define dysfunctional immune responses in severe COVID-19 patients [J]. Cell Rep, 2021, 34(11): 108863.
55	Reizine F, Lesouhaitier M, Gregoire M, et al. SARS-CoV-2-induced ARDS associates with MDSC expansion, lymphocyte dysfunction, and arginine shortage [J]. J Clin Immunol, 2021, 41(3): 515-525.
56	Jiménez-Cortegana C, Liró J, Palazón-Carrión N, et al. Increased blood monocytic myeloid derived suppressor cells but low regulatory t lymphocytes in patients with mild COVID-19 [J]. Viral Immunol, 2021, 34(9): 639-645.
57	Sacchi A, Grassi G, Bordoni V, et al. Early expansion of myeloid-derived suppressor cells inhibits SARS-CoV-2 specific T-cell response and may predict fatal COVID-19 outcome [J]. Cell Death Dis, 2020, 11(10): 921.
58	Agrati C, Sacchi A, Bordoni V, et al. Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19) [J]. Cell Death Differ, 2020, 27(11): 3196-3207.
59	Park MJ, Lee SH, Kim EK, et al. Interleukin-10 produced by myeloid-derived suppressor cells is critical for the induction of Tregs and attenuation of rheumatoid inflammation in mice [J]. Sci Rep, 2018, 8(1): 3753.
60	Tebartz C, Horst SA, Sparwasser T, et al. A major role for myeloid-derived suppressor cells and a minor role for regulatory T cells in immunosuppression during Staphylococcus aureus infection [J]. J Immunol, 2015, 194(3): 1100-1111.
61	Heim CE, Vidlak D, Scherr TD, et al. Myeloid-derived suppressor cells contribute to. Staphylococcus aureus orthopedic biofilm infection [J]. J Immunol, 2014, 192(8): 3778-3792.
62	Zhang C, Lei GS, Shao S, et al. Accumulation of myeloid-derived suppressor cells in the. lungs during Pneumocystis pneumonia [J]. Infect Immun, 2012, 80(10): 3634-3641.
63	Sander LE, Sackett SD, Dierssen U, et al. Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function [J]. J Exp Med, 2010, 207(7): 1453-1464.
64	Chen J, Cai S, Li R, et al. Blockade of Cycloxygenase-2 ameliorates sepsis induced immune-suppression by regulating myeloid-derived suppressor cells [J]. Int Immunopharmacol, 2022, 104: 108506.
65	Xue Y, Xu Y, Liu X, et al. Correction to: ferumoxytol attenuates the function of MDSCs to ameliorate LPS-induced immunosuppression in sepsis [J]. Nanoscale Res Lett, 2022, 17(1): 3.
66	Liu T, Yang F, Xie J, et al. All-trans-retinoic acid restores CD4+ T cell response after sepsis by inhibiting the expansion and activation of myeloid-derived suppressor cells [J]. Mol Immunol, 2021, 136: 8-15.
67	Luo M, Wang H, Liu K, et al. IL-1R1 blockade attenuates liver injury through inhibiting the recruitment of myeloid-derived suppressor cells in sepsis [J]. Biochem Biophys Res Commun, 2022, 620: 21-28.
68	Chang S, Kim YH, Kim YJ, et al. Taurodeoxycholate increases the number of myeloid-derived suppressor cells that ameliorate sepsis in mice [J]. Front Immunol, 2018, 9: 1984.
69	McClure C, Brudecki L, Ferguson DA, et al. MicroRNA 21 (miR-21) and miR-181b couple with NFI-A to generate myeloid-derived suppressor cells and promote immunosuppression in late sepsis [J]. Infect Immun, 2014, 82(9): 3816-3825.
70	McClure C, Ali E, Youssef D, et al. NFI-A disrupts myeloid cell differentiation and maturation in septic mice [J]. J Leukoc Biol, 2016, 99(1): 201-211.
71	McPeak MB, Youssef D, Williams DA, et al. Myeloid cell-specific knockout of NFI-A improves sepsis survival [J]. Infect Immun, 2017, 85(4): e00066-117.
72	Alkhateeb T, Bah I, Kumbhare A, et al. Long non-coding RNA Hotairm1 promotes S100A9 support of MDSC expansion during sepsis [J]. J Clin Cell Immunol, 2020, 11(6): 600.
73	Namkoong H, Ishii M, Fujii H, et al. Clarithromycin expands CD11b+Gr-1+ cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia [J]. PLoS Pathog, 2018, 14(4): e1006955.
74	Derive M, Bouazza Y, Alauzet C, et al. Myeloid-derived suppressor cells control microbial sepsis [J]. Intensive Care Med, 2012, 38(6): 1040-1049.
75	Reizine F, Grégoire M, Lesouhaitier M, et al. Beneficial effects of citrulline enteral administration on sepsis-induced T cell mitochondrial dysfunction [J]. Proc Natl Acad Sci U S A, 2022, 119(8): e2115139119.
76	Wijnands KA, Castermans TM, Hommen MP, et al. Arginine and citrulline and the immune response in sepsis [J]. Nutrients, 2015, 7(3): 1426-1463.
77	Agarwal U, Didelija IC, Yuan Y, et al. Supplemental Citrulline is more efficient than Arginine in increasing systemic Arginine availability in mice [J]. J Nutr, 2017, 147(4): 596-602.

[1]	庄燕, 戴林峰, 张海东, 陈秋华, 聂清芳. 脓毒症患者早期生存影响因素及Cox 风险预测模型构建[J/OL]. 中华危重症医学杂志(电子版), 2024, 17(05): 372-378.
[2]	杨瑾, 刘雪克, 张媛媛, 金钧, 韦瑶. 肠道微生物来源石胆酸对脓毒症相关肝损伤的保护作用[J/OL]. 中华危重症医学杂志(电子版), 2024, 17(04): 265-274.
[3]	张霞, 张瑞, 郑志波, 张勤. 紫草素调控乳酸化修饰和线粒体功能改善脓毒症心肌病小鼠的预后[J/OL]. 中华危重症医学杂志(电子版), 2024, 17(04): 275-284.
[4]	张婧琦, 江洋, 孙佳璐, 唐兴喆, 赵宇飞, 崔颖, 李信响, 戴景月, 傅琳, 彭新桂. 基于肾周CT特征结合血清肌酐水平探讨脓毒症伴急性肾损伤的早期识别[J/OL]. 中华危重症医学杂志(电子版), 2024, 17(04): 285-292.
[5]	李振翮, 魏长青, 甄国栋, 李振富. 脓毒症并发急性呼吸窘迫综合征患者血清S1P、Wnt5a变化及其临床意义[J/OL]. 中华危重症医学杂志(电子版), 2024, 17(04): 293-300.
[6]	何羽. 腔镜微创手术治疗分化型甲状腺癌的研究进展[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(04): 456-458.
[7]	司钦亮, 毕世龙, 焦慧骁, 李世照, 陈哲禹, 武玉东. 精索去分化脂肪肉瘤两例并文献复习[J/OL]. 中华腔镜泌尿外科杂志(电子版), 2024, 18(06): 585-590.
[8]	杨攀, 黄晓寒, 邓才霞, 周利航, 周向东, 罗虎. SMARCA4缺失的胸部未分化肿瘤临床特征及预后分析[J/OL]. 中华肺部疾病杂志(电子版), 2024, 17(04): 529-534.
[9]	任江波, 李丽, 王萍. 阻断PI3K/Akt信号通路促进低表达FoxA2肝脏前体细胞对分化诱导剂应答并朝肝细胞方向分化[J/OL]. 中华细胞与干细胞杂志(电子版), 2024, 14(06): 336-343.
[10]	李彦浇, 梁雷, 金钫, 王智伟. 银杏内酯B通过调控miR-24-3p对人牙周膜干细胞增殖、成骨分化的影响[J/OL]. 中华细胞与干细胞杂志(电子版), 2024, 14(04): 229-235.
[11]	成人脓毒症患者β-内酰胺类抗生素延长输注专家共识编写组. 成人脓毒症患者β-内酰胺类抗生素延长输注专家共识[J/OL]. 中华重症医学电子杂志, 2024, 10(04): 313-324.
[12]	张津, 李欣达, 徐如祥. 神经类器官在大脑常见疾病治疗中的应用及在脊髓损伤修复中的应用前景[J/OL]. 中华脑科疾病与康复杂志(电子版), 2024, 14(05): 257-263.
[13]	陈惠英, 邱敏珊, 邵汉权. 脓毒症诱发肠黏膜屏障功能损伤的风险因素模型构建与应用效果[J/OL]. 中华消化病与影像杂志(电子版), 2024, 14(05): 448-452.
[14]	杨菲, 刘腾飞, 赵志军, 李睿聪, 张颉, 刘妍, 赵珍. 血清维生素水平与分化型甲状腺癌的关联性研究[J/OL]. 中华临床医师杂志(电子版), 2024, 18(07): 633-640.
[15]	傅新露, 李之岳, 卢丹. 妊娠合并结肠癌穿孔致脓毒症休克一例并文献复习[J/OL]. 中华产科急救电子杂志, 2024, 13(04): 227-231.

阅读次数

全文

摘要

选择文件类型/文献管理软件名称

选择包含的内容

Research progress of myeloid derived suppressor cells in sepsis

模态框（Modal）标题

选择文件类型/文献管理软件名称

选择包含的内容

Research progress of myeloid derived suppressor cells in sepsis