Candida-induced granulocytic myeloid-derived suppressor cells are protective against polymicrobial sepsis.
Candida-induced granulocytic myeloid-derived suppressor cells are protective against polymicrobial sepsis.
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多微生物腹腔内感染（IAI）可导致危及生命的败血症，具有显著的发病率和死亡率，特别是当涉及致病性真菌时。我们采用了一种已建立的临床相关的真菌/细菌IAI小鼠模型，并表明使用低毒力念珠菌（即dubliniensis）进行免疫接种可以通过抑制致死性炎症诱导对抗败血症的反应。这种保护依赖于长寿命的Gr-1+多形核白细胞，这些白细胞表现出与髓源性抑制细胞（MDSCs）和训练过的先天免疫一致的特征。在这里，我们的目的是功能和表型表征这些保护性的Gr-1+白细胞。与未免疫的对照组小鼠相比，我们观察到免疫小鼠腹腔内全身和局部CD11b+ Gr-1+细胞水平升高。分离的腹膜Gr-1+细胞表现出显著的MDSC表型，包括t细胞抑制活性增加和MDSC效应活性增加。此外，我们观察到免疫小鼠腹腔内抗炎MDSC细胞因子白细胞介素(IL)-10水平升高，相反，当免疫小鼠的Gr-1+白细胞在攻击前被耗尽时，炎症反应增加。流式细胞术分析显示，免疫小鼠的Ly6G+粒细胞MDSCs （G-MDSCs）比Ly6C+单核细胞MDSCs （M-MDSCs）优先增加。重要的是，G-MDSCs，而不是M-MDSCs，以及IL-10的产生，对致命败血症的全面保护是必需的。根据这些数据，我们得出结论，对多微生物脓毒症具有保护作用的Gr-1+白细胞是真正的MDSCs，并假设MDSCs介导的保护机制包括IL-10消除致死性炎症。多微生物腹腔感染是严重的临床感染，可导致危及生命的败血症，由于涉及复杂和动态的炎症反应，这种感染难以治疗。我们之前的研究表明，用低毒力念珠菌免疫可以对小鼠致命的多微生物脓毒症攻击提供强有力的保护。这种长期保护被发现是由训练的具有类似髓源性抑制细胞（MDSCs）特征的Gr-1+多形核白细胞介导的。在这里，我们明确地将这些细胞定性为MDSCs，并证明它们的保护机制涉及消除致死性炎症，部分是通过抗炎细胞因子白细胞介素(IL)-10的作用。这些研究强调了MDSCs和IL-10在控制急性致死性炎症中的作用，并为训练耐受性免疫反应在败血症临床治疗中的应用提供了支持。
Polymicrobial intra-abdominal infections (IAI) can lead to life-threatening sepsis with significant morbidity and mortality, especially when pathogenic fungi are involved. We have employed an established clinically relevant mouse model of fungal/bacterial IAI and shown that immunization with low-virulence Candida species, that is, Candida dubliniensis, can induce responses that protect against sepsis via the suppression of lethal inflammation. This protection is dependent on long-lived Gr-1+ polymorphonuclear leukocytes that display characteristics consistent with myeloid-derived suppressor cells (MDSCs) and trained innate immunity. Here we aimed to functionally and phenotypically characterize these protective Gr-1+ leukocytes. Compared to nonimmunized control mice, we observed increased levels of CD11b+ Gr-1+ cells systemically and locally in the peritoneal cavity of immunized mice. Isolated peritoneal Gr-1+ cells displayed hallmark MDSC phenotypes including increased T-cell suppressor activity and increased MDSC effector activity. Furthermore, we observed increased levels of the anti-inflammatory MDSC cytokine interleukin (IL)-10 in the peritoneal cavity of immunized mice and, in contrast, increased inflammatory responses when Gr-1+ leukocytes were depleted from immunized mice prior to challenge. Flow cytometric analysis revealed that Ly6G+ granulocytic MDSCs (G-MDSCs) were preferentially increased over Ly6C+ monocytic MDSCs (M-MDSCs) in immunized mice. Importantly, G-MDSCs, but not M-MDSCs, as well as IL-10 production, are required for full protection against lethal sepsis. From these data, we conclude that the Gr-1+ leukocytes that protect against polymicrobial sepsis are bona fide MDSCs and hypothesize that the mechanism of MDSC-mediated protection includes abrogation of lethal inflammation by IL-10. Polymicrobial intra-abdominal infections are serious clinical infections that can lead to life-threatening sepsis, which is difficult to treat in part due to the complex and dynamic inflammatory responses involved. Our prior studies demonstrated that immunization with low-virulence Candida species can provide strong protection against lethal polymicrobial sepsis challenge in mice. This long-lived protection was found to be mediated by trained Gr-1+ polymorphonuclear leukocytes with features resembling myeloid-derived suppressor cells (MDSCs). Here we definitively characterize these cells as MDSCs and demonstrate that their mechanism of protection involves the abrogation of lethal inflammation, in part through the action of the anti-inflammatory cytokine interleukin (IL)-10. These studies highlight the role of MDSCs and IL-10 in controlling acute lethal inflammation and give support for the utility of trained tolerogenic immune responses in the clinical treatment of sepsis.
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影响因子：
17.1
作者：
Highfill SL;Cui Y;Giles AJ;Smith JP;Zhang H;Morse E;Kaplan RN;Mackall CL
通讯作者：
Mackall CL
影响因子：
64.5
作者：
Mitroulis I;Ruppova K;Wang B;Chen LS;Grzybek M;Grinenko T;Eugster A;Troullinaki M;Palladini A;Kourtzelis I;Chatzigeorgiou A;Schlitzer A;Beyer M;Joosten LAB;Isermann B;Lesche M;Petzold A;Simons K;Henry I;Dahl A;Schultze JL;Wielockx B;Zamboni N;Mirtschink P;Coskun Ü;Hajishengallis G;Netea MG;Chavakis T
通讯作者：
Chavakis T
影响因子：
38.9
作者：
Derive, Marc;Bouazza, Youcef;Gibot, Sebastien
通讯作者：
Gibot, Sebastien
影响因子：
20.3
作者：
Movahedi, Kiavash;Guilliams, Martin;Van Ginderachter, Jo A.
通讯作者：
Van Ginderachter, Jo A.
影响因子：
6.7
作者：
Namkoong H;Ishii M;Fujii H;Yagi K;Asami T;Asakura T;Suzuki S;Hegab AE;Kamata H;Tasaka S;Atarashi K;Nakamoto N;Iwata S;Honda K;Kanai T;Hasegawa N;Koyasu S;Betsuyaku T
通讯作者：
Betsuyaku T