Human Myeloid-derived Suppressor Cells Derived From the Bone Marrow Are Decreased With Age but Maintain Their Functional Ability

Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells developing from myeloid progenitors, which are enriched in pathological conditions such as cancer, and are known toinhibit the functions of effector T cells. During aging, several changes occur both at the adaptive and innate immune system level, in a process defined as immunoscenescence. In particular, the low-grade inflammation state observed in the elderly appears to affect hematopoiesis. We previously demonstrated that the combination of GM-CSF and G-CSF drives the in vitro generation of bone marrow-derived MDSCs (BM-MDSCs) from precursors present in human bone marrow aspirates of healthy donors, and that these cells are endowed with a strong immune suppressive ability, resembling that of cancer-associated MDSCs. In the present work we investigated BM-MDSCs induction and functional ability in a cohort of pediatric versus elderly donors. To this aim, we analyzed the differences in maturation stages and ability to suppress T cell proliferation. We found that the ex vivo distribution of myeloid progenitors is similar between pediatric and elderly individuals, whereas after cytokine treatment a significant reduction in the more immature compartment is observed in the elderly. Despite the decreased frequency, BM-MDSCs maintain their suppressive capacity in aged donors. Taken together, these results indicate that in vitro induction of MDSCs from the BM is reduced with aging and opens new hypotheses onthe role of age-related processes in myelopoiesis.

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Human myeloid-derived suppressor cells derived from the bone marrow maintain their functional ability with aging but have a reduced frequency of induction

10.21203/rs.3.rs-39610/v2 ◽

2020 ◽

Author(s):

Sara Magri ◽

Elena Masetto ◽

Samantha Solito ◽

Samuela Francescato ◽

Elisa Belluzzi ◽

...

Keyword(s):

Bone Marrow ◽

Functional Ability ◽

Suppressor Cells ◽

The Elderly ◽

System Level ◽

Low Grade ◽

Myeloid Derived Suppressor Cells ◽

Age Related ◽

Myeloid Progenitors

Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells developing from myeloid progenitors, which are enriched in pathological conditions such as cancer, and are known to inhibit the functions of effector T cells. During aging, several changes occur both at the adaptive and innate immune system level, in a process defined as immunoscenescence. In particular, the low-grade inflammation state observed in the elderly appears to affect hematopoiesis. We previously demonstrated that the combination of GM-CSF and G-CSF drives the in vitro generation of bone marrow-derived MDSCs (BM-MDSCs) from precursors present in human bone marrow aspirates of healthy donors, and that these cells are endowed with a strong immune suppressive ability, resembling that of cancer-associated MDSCs. In the present work we investigated BM-MDSCs induction and functional ability in a cohort of pediatric versus elderly donors. To this aim, we analyzed the differences in maturation stages and ability to suppress T cell proliferation. We found that the ex vivo distribution of myeloid progenitors is similar between pediatric and elderly individuals, whereas after cytokine treatment a significant reduction in the more immature compartment is observed in the elderly. Despite the decreased frequency, BM-MDSCs maintain their suppressive capacity in aged donors. Taken together, these results indicate that in vitro induction of MDSCs from the BM is reduced with aging and opens new hypotheses on the role of age-related processes in myelopoiesis.

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Human MDSCs derived from the bone marrow maintain their functional ability but have a reduced frequency of induction in the elderly compared to pediatric donors

10.21203/rs.3.rs-39610/v3 ◽

2020 ◽

Author(s):

Sara Magri ◽

Elena Masetto ◽

Samantha Solito ◽

Samuela Francescato ◽

Elisa Belluzzi ◽

...

Keyword(s):

Bone Marrow ◽

Functional Ability ◽

Ex Vivo ◽

Suppressor Cells ◽

The Elderly ◽

System Level ◽

Low Grade ◽

Age Related ◽

Myeloid Progenitors

Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells developing from myeloid progenitors, which are enriched in pathological conditions such as cancer, and are known to inhibit the functions of effector T cells. During aging, several changes occur both at the adaptive and innate immune system level, in a process defined as immunoscenescence. In particular, the low-grade inflammation state observed in the elderly appears to affect hematopoiesis. We previously demonstrated that the combination of GM-CSF and G-CSF drives the in vitro generation of bone marrow-derived MDSCs (BM-MDSCs) from precursors present in human bone marrow aspirates of healthy donors, and that these cells are endowed with a strong immune suppressive ability, resembling that of cancer-associated MDSCs. In the present work we investigated BM-MDSCs induction and functional ability in a cohort of pediatric versus elderly donors. To this aim, we analyzed the differences in maturation stages and ability to suppress T cell proliferation. We found that the ex vivo distribution of myeloid progenitors is similar between pediatric and elderly individuals, whereas after cytokine treatment a significant reduction in the more immature compartment is observed in the elderly. Despite the decreased frequency, BM-MDSCs maintain their suppressive capacity in aged donors. Taken together, these results indicate that in vitro induction of MDSCs from the BM is reduced with aging and opens new hypotheses on the role of age-related processes in myelopoiesis.

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Human MDSCs derived from the bone marrow maintain their functional ability but have a reduced frequency of induction in the elderly compared to pediatric donors

Immunity & Ageing ◽

10.1186/s12979-020-00199-5 ◽

2020 ◽

Vol 17 (1) ◽

Cited By ~ 1

Author(s):

Sara Magri ◽

Elena Masetto ◽

Samantha Solito ◽

Samuela Francescato ◽

Elisa Belluzzi ◽

...

Keyword(s):

Bone Marrow ◽

Functional Ability ◽

Ex Vivo ◽

Suppressor Cells ◽

The Elderly ◽

System Level ◽

Low Grade ◽

Age Related ◽

Myeloid Progenitors

AbstractMyeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells developing from myeloid progenitors, which are enriched in pathological conditions such as cancer, and are known to inhibit the functions of effector T cells. During aging, several changes occur both at the adaptive and innate immune system level, in a process defined as immunoscenescence. In particular, the low-grade inflammation state observed in the elderly appears to affect hematopoiesis. We previously demonstrated that the combination of GM-CSF and G-CSF drives the in vitro generation of bone marrow-derived MDSCs (BM-MDSCs) from precursors present in human bone marrow aspirates of healthy donors, and that these cells are endowed with a strong immune suppressive ability, resembling that of cancer-associated MDSCs. In the present work we investigated BM-MDSCs induction and functional ability in a cohort of pediatric versus elderly donors. To this aim, we analyzed the differences in maturation stages and ability to suppress T cell proliferation. We found that the ex vivo distribution of myeloid progenitors is similar between pediatric and elderly individuals, whereas after cytokine treatment a significant reduction in the more immature compartment is observed in the elderly. Despite the decreased frequency, BM-MDSCs maintain their suppressive capacity in aged donors. Taken together, these results indicate that in vitro induction of MDSCs from the BM is reduced with aging and opens new hypotheses on the role of age-related processes in myelopoiesis.

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Granulocytic Myeloid-Derived Suppressor Cells Aggravate Tuberculosis Caused by Hypervirulent Mycobacteria

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa708 ◽

2020 ◽

Author(s):

Caio César Barbosa Bomfim ◽

Eduardo Pinheiro Amaral ◽

Igor Santiago-Carvalho ◽

Gislane Almeida Santos ◽

Érika Machado Salles ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

Cell Function ◽

Pulmonary Inflammation ◽

Bacterial Load ◽

Suppressor Cells ◽

Myeloid Cell ◽

Partial Recovery ◽

Myeloid Derived Suppressor Cells

Abstract Background The role of myeloid-derived suppressor cells (MDSCs) in severe tuberculosis patients who suffer from uncontrolled pulmonary inflammation caused by hypervirulent mycobacterial infection remains unclear. Methods This issue was addressed using C57BL/6 mice infected with highly virulent Mycobacterium bovis strain MP287/03. Results CD11b +GR1 int population increased in the bone marrow, blood and lungs during advanced disease. Pulmonary CD11b +GR1 int (Ly6G intLy6C int) cells showed granularity similar to neutrophils and expressed immature myeloid cell markers. These immature neutrophils harbored intracellular bacilli and were preferentially located in the alveoli. T cell suppression occurred concomitantly with CD11b +GR1 int cell accumulation in the lungs. Furthermore, lung and bone-marrow GR1 + cells suppressed both T cell proliferation and IFN-γ production in vitro. Anti-GR1 therapy given when MDSCs infiltrated the lungs prevented expansion and fusion of primary pulmonary lesions and the development of intragranulomatous caseous necrosis, along with increased mouse survival and partial recovery of T cell function. Lung bacterial load was reduced by anti-GR1 treatment, but mycobacteria released from the depleted cells proliferated extracellularly in the alveoli, forming cords and clumps. Conclusions Granulocytic MDSCs massively infiltrate the lungs during infection with hypervirulent mycobacteria, promoting bacterial growth and the development of inflammatory and necrotic lesions, and are promising targets for host-directed therapies.

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MicroRNA 21 (miR-21) and miR-181b Couple with NFI-A To Generate Myeloid-Derived Suppressor Cells and Promote Immunosuppression in Late Sepsis

Infection and Immunity ◽

10.1128/iai.01495-14 ◽

2014 ◽

Vol 82 (9) ◽

pp. 3816-3825 ◽

Cited By ~ 59

Author(s):

Clara McClure ◽

Laura Brudecki ◽

Donald A. Ferguson ◽

Zhi Q. Yao ◽

Jonathan P. Moorman ◽

...

Keyword(s):

Bone Marrow ◽

Innate Immunity ◽

Transforming Growth Factor ◽

Ex Vivo ◽

Cecal Ligation ◽

Myeloid Cells ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Cell Repertoire ◽

Myeloid Progenitors

ABSTRACTThe sepsis initial hyperinflammatory reaction, if not treated early, shifts to a protracted state of immunosuppression that alters both innate and adaptive immunity and is associated with elevated mortality. Myeloid-derived suppressor cells (MDSCs) are myeloid progenitors and precursors that fail to differentiate into mature innate-immunity cells and are known for their potent immunosuppressive activities. We previously reported that murine MDSCs expand dramatically in the bone marrow during late sepsis, induced by cecal ligation and puncture, and demonstrated that they contribute to late-sepsis immunosuppression. However, the molecular mechanism responsible for generating these immature Gr1+CD11b+myeloid cells during sepsis remains unknown. We show here that sepsis generates a microRNA (miRNA) signature that expands MDSCs. We found that miRNA 21 (miR-21) and miR-181b expression is upregulated in early sepsis and sustained in late sepsis. Importantly, we found that simultaneousin vivoblockade of both miRNAs via antagomiR (a chemically modified miRNA inhibitor) injection after sepsis initiation decreased the bone marrow Gr1+CD11b+myeloid progenitors, improved bacterial clearance, and reduced late-sepsis mortality by 74%. Gr1+CD11b+cells isolated from mice injected with antagomiRs were able to differentiateex vivointo macrophages and dendritic cells and produced smaller amounts of the immunosuppressive interleukin 10 (IL-10) and transforming growth factor β (TGF-β) after stimulation with bacterial lipopolysaccharide, suggesting that immature myeloid cells regained their maturation potential and have lost their immunosuppressive activity. In addition, we found that the protein level of transcription factor NFI-A, which plays a role in myeloid cell differentiation, was increased during sepsis and that antagomiR injection reduced its expression. Moreover, knockdown of NFI-A in the Gr1+CD11b+cells isolated from late-septic mice increased their maturation potential and reduced their production of the immunosuppressive mediators, similar to antagomiR injection. These data support the hypothesis that sepsis reprograms myeloid cells and thus alters the innate immunity cell repertoire to promote immunosuppression, and they demonstrate that this process can be reversed by targeting miR-21 and miR-181b to improve late-sepsis survival.

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Suppression of Proteoglycan-Induced Autoimmune Arthritis by Myeloid-Derived Suppressor Cells Generated In Vitro from Murine Bone Marrow

PLoS ONE ◽

10.1371/journal.pone.0111815 ◽

2014 ◽

Vol 9 (11) ◽

pp. e111815 ◽

Cited By ~ 19

Author(s):

Júlia Kurkó ◽

András Vida ◽

Tímea Ocskó ◽

Beata Tryniszewska ◽

Tibor A. Rauch ◽

...

Keyword(s):

Bone Marrow ◽

Suppressor Cells ◽

Autoimmune Arthritis ◽

Myeloid Derived Suppressor Cells ◽

Murine Bone Marrow

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In Vitro 3D Staphylococcus aureus Abscess Communities Induce Bone Marrow Cells to Expand into Myeloid-Derived Suppressor Cells

Pathogens ◽

10.3390/pathogens10111446 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1446

Author(s):

Marloes I. Hofstee ◽

Anja Heider ◽

Sonja Häckel ◽

Caroline Constant ◽

Martijn Riool ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Bone Marrow ◽

T Cell ◽

Bone Marrow Cells ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Cell Numbers ◽

Biomarker Analysis ◽

Marrow Cells

Staphylococcus aureus is the main causative pathogen of subcutaneous, bone, and implant-related infections, forming structures known as staphylococcal abscess communities (SACs) within tissues that also contain immunosuppressive myeloid-derived suppressor cells (MDSCs). Although both SACs and MDSCs are present in chronic S. aureus infections, it remains unknown whether SACs directly trigger MDSC expansion. To investigate this, a previously developed 3D in vitro SAC model was co-cultured with murine and human bone marrow cells. Subsequently, it was shown that SAC-exposed human CD11blow/− myeloid cells or SAC-exposed murine CD11b+ Gr-1+ cells were immunosuppressive mainly by reducing absolute CD4+ and CD8α+ T cell numbers, as shown in T cell proliferation assays and with flow cytometry. Monocytic MDSCs from mice with an S. aureus bone infection also strongly reduced CD4+ and CD8α+ T cell numbers. Using protein biomarker analysis and an immunoassay, we detected in SAC–bone marrow co-cultures high levels of GM-CSF, IL-6, VEGF, IL-1β, TNFα, IL-10, and TGF-β. Furthermore, SAC-exposed neutrophils expressed Arg-1 and SAC-exposed monocytes expressed Arg-1 and iNOS, as shown via immunofluorescent stains. Overall, this study showed that SACs cause MDSC expansion from bone marrow cells and identified possible mediators to target as an additional strategy for treating chronic S. aureus infections.

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Swertianolin ameliorates immune dysfunction in sepsis via blocking the immunosuppressive function of myeloid- derived suppressor cells

European Journal of Histochemistry ◽

10.4081/ejh.2021.3292 ◽

2021 ◽

Vol 65 (3) ◽

Author(s):

Zongfang Ren ◽

Haoren Tang ◽

Linjun Wan ◽

Xing Liu ◽

Ning Tang ◽

...

Keyword(s):

Bone Marrow ◽

Cecal Ligation ◽

Cell Activity ◽

Suppressor Cells ◽

Interleukin 10 ◽

Myeloid Derived Suppressor Cells ◽

Sepsis Model ◽

Sepsis Induction ◽

Quality Threshold

In this study, we studied the long-term proliferation trajectory of myeloid-derived suppressor cells (MDSCs) in murine sepsis model and investigated whether swertianolin could modulate the immunosuppressive function of MDSCs. A murine sepsis model was established by cecal ligation and perforation (CLP), according to the Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS) guidelines. The bone marrow and spleen of the mice were collected at 24 h, 72 h, 7 and 15 d after sepsis induction. The proportions of monocytic-MDSCs (M-MDSCs; CD11b+LY6G-LY6Chi) and granulocytic-MDSCs (G-MDSC, CD11b+ Ly6G+ Ly6Clow) were analyzed by flow cytometry. Then, we have investigated whether swertianolin could modulate the immunosuppressive function of MDSCs in in vitro experiments. G-MDSCs and M-MDSCs increased acutely after sepsis with high levels sustained over a long period of time. G-MDSCs were the main subtype identified in the murine model of sepsis with polymicrobial peritonitis. Furthermore, it was found that swertianolin reduced significantly interleukin-10 (IL-10), nitric oxide (NO), reactive oxygen species (ROS), and arginase production in MDSCs, while reducing MDSC proliferation and promoting MDSC differentiation into dendritic cells. Swertianolin also improved T-cell activity by blocking the immunosuppressive effect of MDSCs. Both subsets of MDSCs significantly increased in the bone marrow and spleen of the mice with sepsis, with G-MDSCs being the main subtype identified. Swertianolin effectively regulated the functions of MDSCs and reduced immune suppression.

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COX2/mPGES1/PGE2pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1612920114 ◽

2017 ◽

Vol 114 (5) ◽

pp. 1117-1122 ◽

Cited By ~ 147

Author(s):

Victor Prima ◽

Lyudmila N. Kaliberova ◽

Sergey Kaliberov ◽

David T. Curiel ◽

Sergei Kusmartsev

Keyword(s):

Bone Marrow ◽

Cancer Progression ◽

Bone Marrow Cells ◽

Myeloid Cells ◽

Suppressor Cells ◽

Prostaglandin E ◽

Tumor Escape ◽

Myeloid Derived Suppressor Cells ◽

Tumor Associated Macrophages

In recent years, it has been established that programmed cell death protein ligand 1 (PD-L1)–mediated inhibition of activated PD-1+T lymphocytes plays a major role in tumor escape from immune system during cancer progression. Lately, the anti–PD-L1 and –PD-1 immune therapies have become an important tool for treatment of advanced human cancers, including bladder cancer. However, the underlying mechanisms of PD-L1 expression in cancer are not fully understood. We found that coculture of murine bone marrow cells with bladder tumor cells promoted strong expression of PD-L1 in bone marrow–derived myeloid cells. Tumor-induced expression of PD-L1 was limited to F4/80+macrophages and Ly-6C+myeloid-derived suppressor cells. These PD-L1–expressing cells were immunosuppressive and were capable of eliminating CD8 T cells in vitro. Tumor-infiltrating PD-L1+cells isolated from tumor-bearing mice also exerted morphology of tumor-associated macrophages and expressed high levels of prostaglandin E2(PGE2)-forming enzymes microsomal PGE2synthase 1 (mPGES1) and COX2. Inhibition of PGE2formation, using pharmacologic mPGES1 and COX2 inhibitors or genetic overexpression of PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), resulted in reduced PD-L1 expression. Together, our study demonstrates that the COX2/mPGES1/PGE2pathway involved in the regulation of PD-L1 expression in tumor-infiltrating myeloid cells and, therefore, reprogramming of PGE2metabolism in tumor microenvironment provides an opportunity to reduce immune suppression in tumor host.

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Age-related Changes in Bone Marrow Mesenchymal Stromal Cells

Cell Transplantation ◽

10.1177/0963689717721201 ◽

2017 ◽

Vol 26 (9) ◽

pp. 1520-1529 ◽

Cited By ~ 64

Author(s):

Payal Ganguly ◽

Jehan J. El-Jawhari ◽

Peter V. Giannoudis ◽

Agata N. Burska ◽

Frederique Ponchel ◽

...

Keyword(s):

Bone Marrow ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Current Knowledge ◽

The Elderly ◽

Cellular Level ◽

Age Related ◽

Population Doublings

Aging at the cellular level is a complex process resulting from accumulation of various damages leading to functional impairment and a reduced quality of life at the level of the organism. With a rise in the elderly population, the worldwide incidence of osteoporosis (OP) and osteoarthritis (OA) has increased in the past few decades. A decline in the number and “fitness” of mesenchymal stromal cells (MSCs) in the bone marrow (BM) niche has been suggested as one of the factors contributing to bone abnormalities in OP and OA. It is well recognized that MSCs in vitro acquire culture-induced aging features such as gradual telomere shortening, increased numbers of senescent cells, and reduced resistance to oxidative stress as a result of serial population doublings. In contrast, there is only limited evidence that human BM-MSCs “age” similarly in vivo. This review compares the various aspects of in vitro and in vivo MSC aging and suggests how our current knowledge on rejuvenating cultured MSCs could be applied to develop future strategies to target altered bone formation processes in OP and OA.

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