RESUMEN
Myeloid-derived suppressor cells (MDSCs) play an essential role in suppressing the antitumor activity of T lymphocytes in solid tumors, thus representing an attractive therapeutic target to enhance the efficacy of immunotherapy. However, the differences in protein expression between MDSCs and their physiological counterparts, particularly polymorphonuclear neutrophils (PMNs), remain inadequately characterized, making the specific identification and targeting of MDSCs difficult. PMNs and PMN-MDSCs share markers such as CD11b+CD14-CD15+/CD66b+, and some MDSC-enriched markers are emerging, such as LOX-1 and CD84. More proteomics studies are needed to identify the signature and markers for MDSCs. Recently, we reported the induced differentiation of isogenic PMNs or MDSCs (referred to as iPMNs and iMDSCs, respectively) from the human promyelocytic cell line HL60. Here, we profiled the global proteomics and membrane proteomics of these cells with quantitative mass spectrometry, which identified a 41-protein signature ("cluster 6") that was upregulated in iMDSCs compared with HL60 and iPMN. We further integrated our cell line-based proteomics data with a published proteomics dataset of normal human primary monocytes and monocyte-derived MDSCs induced by cancer-associated fibroblasts. The analysis identified a 38-protein signature that exhibits an upregulated expression pattern in MDSCs compared with normal monocytes or PMNs. These signatures may provide a hypothesis-generating platform to identify protein biomarkers that phenotypically distinguish MDSCs from their healthy counterparts, as well as potential therapeutic targets that impair MDSCs without harming normal myeloid cells.
Asunto(s)
Diferenciación Celular , Células Supresoras de Origen Mieloide , Neutrófilos , Proteómica , Humanos , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/citología , Neutrófilos/metabolismo , Neutrófilos/citología , Proteómica/métodos , Células HL-60 , Línea CelularRESUMEN
Immune-suppressive effects of myeloid-derived suppressor cells (MDSCs) are well characterized during anti-tumor immunity. The complex mechanisms promoting MDSC development and their regulatory effects during autoimmune diseases are less understood. We demonstrate that the endogenous alarmin S100A8/A9 reprograms myeloid cells to a T cell suppressing phenotype during autoimmune arthritis. Treatment of myeloid precursors with S100-alarmins during differentiation induces MDSCs in a Toll-like receptor 4-dependent manner. Consequently, knockout of S100A8/A9 aggravates disease activity in collagen-induced arthritis due to a deficit of MDSCs in local lymph nodes, which could be corrected by adoptive transfer of S100-induced MDSCs. Blockade of MDSC function in vivo aggravates disease severity in arthritis. Therapeutic application of S100A8 induces MDSCs in vivo and suppresses the inflammatory phenotype of S100A9ko mice. Accordingly, the interplay of T cell-mediated autoimmunity with a defective innate immune regulation is crucial for autoimmune arthritis, which should be considered for future innovative therapeutic options.
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Artritis , Calgranulina A , Calgranulina B , Células Supresoras de Origen Mieloide , Animales , Ratones , Artritis/inmunología , Artritis/metabolismo , Artritis/patología , Linfocitos T/citología , Linfocitos T/inmunología , Células Supresoras de Origen Mieloide/citología , Células Supresoras de Origen Mieloide/inmunología , Modelos Animales de Enfermedad , Diferenciación Celular , Óxido Nítrico/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Calgranulina A/metabolismo , Calgranulina B/metabolismoRESUMEN
OBJECTIVE: This study analyzed the effect of HDAC inhibitor, trichostatin A (TSA), in inducing granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated bone marrow (BM) cell differentiation to myeloid-derived suppressor cells (MDSCs) in vitro and in vivo. METHODS: BM cell differentiation to CD11b + GR-1 + MDSCs was achieved by in vitro culture with TSA and GM-CSF, and the collected cells were analyzed by mixed lymphocyte culture to identify suppressive actions against effector T cells. RT-PCR and ELISA were conducted to analyze the CCL5 mRNA and protein levels in TSA + GM-CSF + BM, GR-1 + MDSCs and GR-1 + MDSC + CCL5 groups. The survival of cardiac grafts was compared between groups. RESULTS: TSA was beneficial for the GM-CSF-mediated BM differentiation to CD11b + GR-1 + MDSCs. Adoptive transfer of GR-1 + MDSCs was powerful in suppressing CD4 + CD25-T cell proliferation and the effect was mediated by iNOS and HO-1; it also increased CCL5 gradient concentration between grafts and plasma to recruit Treg to grafts and prolong the survival of the grafts. Survival analysis revealed that the survival of grafts after adoptive transfer of GR-1 + MDSCs could be prolonged. CONCLUSION: This study helps in further research on the application value of MDSCs in the field of transplant, and may provide a new thought for the cell therapy in inducing immune tolerance in organ transplant.
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Supervivencia de Injerto , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Trasplante de Corazón , Ácidos Hidroxámicos , Células Supresoras de Origen Mieloide , Animales , Ratones , Médula Ósea , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Ácidos Hidroxámicos/farmacología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Células Supresoras de Origen Mieloide/citologíaRESUMEN
Myeloid-derived suppressor cells (MDSCs) are generated under biological stress such as cancer, inflammatory tissue damage, and viral infection. In recent years, with occurrence of global infectious diseases, new discovery on MDSCs functions has been significantly expanded during viral infection and COVID-19. For a successful viral infection, pathogens viruses develop immune evasion strategies to avoid immune recognition. Numerous viruses induce the differentiation and expansion of MDSCs in order to suppress host immune responses including natural killer cells, antigen presenting cells, and T-cells. Moreover, MDSCs play an important role in regulation of immunopathogenesis by balancing viral infection and tissue damage. In this review article, we describe the overview of immunomodulation and genetic regulation of MDSCs during viral infection in the animal model and human studies. In addition, we include up-to-date review of role of MDSCs in SARS-CoV-2 infection and COVID-19. Finally, we discuss potential therapeutics targeting MDSCs.
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Inmunomodulación/inmunología , Macrófagos/inmunología , Células Supresoras de Origen Mieloide/inmunología , Neutrófilos/inmunología , SARS-CoV-2/inmunología , Animales , COVID-19/inmunología , Modelos Animales de Enfermedad , Humanos , Evasión Inmune/inmunología , Macrófagos/citología , Monocitos/citología , Monocitos/inmunología , Células Supresoras de Origen Mieloide/citologíaRESUMEN
Background: FcγRIIB, the sole inhibitory receptor of the Fc gamma receptor family, plays pivotal roles in innate and adaptive immune responses. However, the expression and function of FcγRIIB in myeloid-derived suppressor cells (MDSCs) remains unknown. This study aimed to investigate whether and how FcγRIIB regulates the immunosuppressive activity of MDSCs during cancer development. Methods: The MC38 and B16-F10 tumor-bearing mouse models were established to investigate the role of FcγRIIB during tumor progression. FcγRIIB-deficient mice, adoptive cell transfer, mRNA-sequencing and flow cytometry analysis were used to assess the role of FcγRIIB on immunosuppressive activity and differentiation of MDSCs. Results: Here we show that FcγRIIB was upregulated in tumor-infiltrated MDSCs. FcγRIIB-deficient mice showed decreased accumulation of MDSCs in the tumor microenvironment (TME) compared with wild-type mice. FcγRIIB was required for the differentiation and immunosuppressive activity of MDSCs. Mechanistically, tumor cell-derived granulocyte-macrophage colony stimulating factor (GM-CSF) increased the expression of FcγRIIB on hematopoietic progenitor cells (HPCs) by activating specificity protein 1 (Sp1), subsequently FcγRIIB promoted the generation of MDSCs from HPCs via Stat3 signaling. Furthermore, blockade of Sp1 dampened MDSC differentiation and infiltration in the TME and enhanced the anti-tumor therapeutic efficacy of gemcitabine. Conclusion: These results uncover an unrecognized regulatory role of the FcγRIIB in abnormal differentiation of MDSCs during cancer development and suggest a potential therapeutic target for anti-tumor therapy.
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Carcinogénesis , Diferenciación Celular , Células Supresoras de Origen Mieloide/citología , Receptores de IgG/fisiología , Escape del Tumor , Adulto , Animales , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Células Supresoras de Origen Mieloide/inmunología , Receptores de IgG/deficiencia , Receptores de IgG/metabolismo , Transducción de SeñalRESUMEN
Accumulating evidence has shown that cancer stroma and BM-derived cells (BMDCs) in the tumor microenvironment (TME) play vital roles in tumor progression. However, the mechanism by which oral cancer stroma recruits any particular subset of BMDCs remains largely unknown. Here, we sought to identify the subset of BMDCs that is recruited by cancer stroma. We established a sequential transplantation model in BALB/c nude mice, including (a) BM transplantation of GFP-expressing cells and (b) coxenografting of patient-derived stroma (PDS; 2 cases, designated PDS1 and PDS2) with oral cancer cells (HSC-2). As controls, xenografting was performed with HSC-2 alone or in combination with normal human dermal fibroblasts (HDF). PDS1, PDS2, and HDF all promoted BMDC migration in vitro and recruitment in vivo. Multicolor immunofluorescence revealed that the PDS coxenografts recruited Arginase-1+CD11b+GR1+GFP+ cells, which are myeloid-derived suppressor cells (MDSCs), to the TME, whereas the HDF coxenograft did not. Screening using microarrays revealed that PDS1 and PDS2 expressed CCL2 mRNA (encoding C-C motif chemokine ligand 2) at higher levels than did HDF. Indeed, PDS xenografts contained significantly higher proportions of CCL2+ stromal cells and CCR2+Arginase-1+CD11b+GR1+ MDSCs (as receiver cells) than the HDF coxenograft. Consistently, a CCL2 synthesis inhibitor and a CCR2 antagonist significantly inhibited the PDS-driven migration of BM cells in vitro. Furthermore, i.p. injection of the CCR2 antagonist to the PDS xenograft models significantly reduced the CCR2+Arginase-1+CD11b+GR1+ MDSC infiltration to the TME. In conclusion, oral cancer stroma-secreted CCL2 is a key signal for recruiting CCR2+ MDSCs from BM to the TME.
Asunto(s)
Quimiocina CCL2/metabolismo , Células Supresoras de Origen Mieloide , Microambiente Tumoral/fisiología , Animales , Línea Celular Tumoral , Células Cultivadas , Femenino , Humanos , Ratones , Ratones Desnudos , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Células Supresoras de Origen Mieloide/citología , Células Supresoras de Origen Mieloide/metabolismoRESUMEN
OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) are heterogeneous cells which can suppress T-cell functionality. Herein, we evaluated the functional importance of MDSCs in the context of kidney ischemia-reperfusion injury (IRI) and explored their ability to regulate innate and adaptive immune cell function in this context. METHODS: The differentiation of MDSCs was induced in vitro by treating cells with GM-CSF and interferon (IFN)-γ. In a murine model of renal IRI, serum creatinine and blood urea nitrogen values were measured to monitor kidney function, while histopathological and immunohistochemical approaches were used to assess kidney injury severity. In addition, flow cytometry was employed to assess the phenotypes and apoptosis of kidney cells in these mice. RESULTS: MDSCs induced by treatment with GM-CSF + IFN-γ could suppress T-cell functionality in vitro. The adoptive transfer of these MDSCs into an IRI mouse model system enhanced kidney damage and impaired renal function following the recruitment of these cells to renal tissues in these mice. Following such adoptive transfer, the relative frequency of MDSCs with a CD11b+Ly6G-Ly6Chigh monocytic-MDSC phenotype decreased, whereas cells with a CD11b+Ly6G+Ly6Clow polymorphonuclear-MDSC phenotype become more prevalent within kidney tissues following IRI. Adoptive transfer also coincided with increased frequencies of macrophages and dendritic cells (DCs) in the kidney tissues. This suggested that M-MDSCs contributed to early-stage renal IRI damage by differentiating into these deleterious cell types. However, MDSC-induced suppression of CD4+ and CD8+ T-cell infiltration was not sufficient to prevent the deterioration of renal function in these mice. CONCLUSIONS: Herein, we successfully developed a protocol wherein MDSCs were differentiated in vitro through combination GM-CSF/IFN-γ treatment. When these MDSCs were subsequently adoptively transferred into a murine model of renal IRI, they aggravated kidney damage, likely owing to the differentiation of M-MDSCs into deleterious macrophages and DCs.
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Inmunidad Innata , Interferón gamma/fisiología , Riñón/irrigación sanguínea , Células Supresoras de Origen Mieloide/citología , Daño por Reperfusión/patología , Traslado Adoptivo , Animales , Apoptosis/inmunología , Proliferación Celular , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Daño por Reperfusión/inmunología , Daño por Reperfusión/terapia , Linfocitos T/inmunologíaRESUMEN
Myeloid-derived suppressor cells (MDSCs) are derived from bone marrow progenitor cells commonly, which is a heterogeneous cell group composed of immature granulocytes, dendritic cells, macrophages and early undifferentiated bone marrow precursor cells. Its differentiation and immunosuppressive function are regulated by complex network signals, but the specific regulation mechanisms are not yet fully understood. In this study, we found that in mouse of Lewis lung cancer xenograft, long non-coding RNA Snhg6 (lncRNA Snhg6) was highly expressed in tumor-derived MDSCs compared with spleen-derived MDSCs. LncRNA Snhg6 facilitated the differentiation of CD11b+ Ly6G- Ly6Chigh monocytic MDSCs (Mo-MDSCs) rather than CD11b+ Ly6G+ Ly6Clow polymorphonuclear MDSCs (PMN-MDSCs), but did not affect the immunosuppressive function of MDSCs. Notably, lncRNA Snhg6 could inhibit the expression of EZH2 by ubiquitination pathway at protein level rather than mRNA level during the differentiation of mouse bone marrow cells into MDSCs in vitro. EZH2 may be an important factor in the regulation of lncRNA Snhg6 to promote the differentiation of Mo-MDSCs. So what we found may provide new ideas and targets for anti-tumor immunotherapy targeting MDSCs.
Asunto(s)
Carcinoma Pulmonar de Lewis/genética , Proteína Potenciadora del Homólogo Zeste 2/genética , Células Supresoras de Origen Mieloide/citología , ARN Largo no Codificante/genética , Animales , Carcinoma Pulmonar de Lewis/metabolismo , Diferenciación Celular , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Regulación Neoplásica de la Expresión Génica , Ratones , Células Supresoras de Origen Mieloide/metabolismo , Estabilidad Proteica , UbiquitinaciónRESUMEN
ABSTRACT: To date, little advances have been made toward new and more effective therapies for pancreatic ductal adenocarcinoma (PDAC). Discovery of prognostic and predictive biomarkers is needed to stratify patients for available treatments and to elucidate how new therapies could be developed. Recent studies have made clear that the immune system is not only affected in the microenvironment of the primary tumor and it is also systemically disrupted in PDAC patients. Under normal circumstances, the immune system is in perfect balance with both proinflammatory and anti-inflammatory components present. In this review, we focus on circulating immunological characteristics including immune cells and their subtypes, cytokines, and immune checkpoints in the peripheral blood not only to understand the poor prognosis of PDAC patients but also to find new leads for new innovative therapies.
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Biomarcadores de Tumor/inmunología , Carcinoma Ductal Pancreático/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Sistema Inmunológico/inmunología , Neoplasias Pancreáticas/inmunología , Animales , Linfocitos B/citología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Biomarcadores de Tumor/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/terapia , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Sistema Inmunológico/citología , Sistema Inmunológico/metabolismo , Inmunoterapia/métodos , Macrófagos/citología , Macrófagos/inmunología , Macrófagos/metabolismo , Células Supresoras de Origen Mieloide/citología , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Neutrófilos/citología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Pronóstico , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
Sepsis is a global health emergency, which is caused by various sources of infection that lead to changes in gene expression, protein-coding, and metabolism. Advancements in "omics" technologies have provided valuable tools to unravel the mechanisms involved in the pathogenesis of this disease. In this study, we performed shotgun mass spectrometry in peripheral blood mononuclear cells (PBMC) from septic patients (N=24) and healthy controls (N=9) and combined these results with two public microarray leukocytes datasets. Through combination of transcriptome and proteome profiling, we identified 170 co-differentially expressed genes/proteins. Among these, 122 genes/proteins displayed the same expression trend. Ingenuity Pathway Analysis revealed pathways related to lymphocyte functions with decreased status, and defense processes that were predicted to be strongly increased. Protein-protein interaction network analyses revealed two densely connected regions, which mainly included down-regulated genes/proteins that were related to the transcription of RNA, translation of proteins, and mitochondrial translation. Additionally, we identified one module comprising of up-regulated genes/proteins, which were mainly related to low-density neutrophils (LDNs). LDNs were reported in sepsis and in COVID-19. Changes in gene expression level were validated using quantitative real-time PCR in PBMCs from patients with sepsis. To further support that the source of the upregulated module of genes/proteins found in our results were derived from LDNs, we identified an increase of this population by flow cytometry in PBMC samples obtained from the same cohort of septic patients included in the proteomic analysis. This study provides new insights into a reprioritization of biological functions in response to sepsis that involved a transcriptional and translational shutdown of genes/proteins, with exception of a set of genes/proteins related to LDNs and host-defense system.
Asunto(s)
Leucocitos Mononucleares/metabolismo , Neutrófilos/metabolismo , Sepsis/metabolismo , Bases de Datos Factuales , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Leucocitos Mononucleares/citología , Células Supresoras de Origen Mieloide/citología , Células Supresoras de Origen Mieloide/metabolismo , Neutrófilos/citología , Mapas de Interacción de Proteínas , Proteómica , Sepsis/genética , Sepsis/inmunologíaRESUMEN
The most fatal malignancy of the central nervous system (CNS) is glioblastoma. Brain cancer is a 'cold' tumor because of fewer immunoregulatory cells and more immunosuppressive cells. Due to the cold nature of brain cancers, conventional treatments which are used to manage glioma patients show little effectiveness. Glioma patients even showed resistance to immune checkpoint blockade (ICB) and no significant efficacy. It has been shown that myeloid-derived suppressor cells (MDSCs) account for approximately 30-50% of the tumor mass in glioma. This study aimed to review MDSC function in brain cancer, as well as possible treatments and related challenges. In brain cancer and glioma, several differences in the context of MDSCs have been reported, including disagreements about the MDSC subtype that has the most inhibitory function in the brain, or inhibitory function of regulatory B cells (Bregs). There are also serious challenges in treating glioma patients. In addition to the cold nature of glioma, there are reports of an increase in MDSCs following conventional chemotherapy treatments. As a result, targeting MDSCs in combination with other therapies, such as ICB, is essential, and recent studies with the combination therapy approach have shown promising therapeutic effects in brain cancer.
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Neoplasias Encefálicas/patología , Glioma/patología , Células Supresoras de Origen Mieloide/citología , Animales , Antineoplásicos/farmacología , Neoplasias Encefálicas/terapia , Resistencia a Antineoplásicos , Glioblastoma/patología , Glioblastoma/terapia , Glioma/terapia , Humanos , Terapia Molecular DirigidaRESUMEN
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells (IMCs) with immunosuppressive functions, whereas IMCs originally differentiate into granulocytes, macrophages, and dendritic cells (DCs) to participate in innate immunity under steady-state conditions. At present, difficulties remain in identifying MDSCs due to lacking of specific biomarkers. To make identification of MDSCs accurately, it also needs to be determined whether having immunosuppressive functions. MDSCs play crucial roles in anti-tumor, angiogenesis, and metastasis. Meanwhile, MDSCs could make close interaction with osteoclasts, osteoblasts, chondrocytes, and other stromal cells within microenvironment of bone and joint, and thereby contributing to poor prognosis of bone-related diseases such as cancer-related bone metastasis, osteosarcoma (OS), rheumatoid arthritis (RA), osteoarthritis (OA), and orthopedic trauma. In addition, MDSCs have been shown to participate in the procedure of bone repair. In this review, we have summarized the function of MDSCs in cancer-related bone metastasis, the interaction with stromal cells within the bone microenvironment as well as joint microenvironment, and the critical role of MDSCs in bone repair. Besides, the promising value of MDSCs in the treatment for bone-related diseases is also well discussed.
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Neoplasias Óseas/patología , Regeneración Ósea/fisiología , Tolerancia Inmunológica/inmunología , Células Supresoras de Origen Mieloide/citología , Artritis Reumatoide/patología , Enfermedades Óseas/patología , Neoplasias Óseas/secundario , Microambiente Celular/fisiología , Células Dendríticas/citología , Granulocitos/citología , Humanos , Inmunidad Innata/inmunología , Macrófagos/citología , Células Supresoras de Origen Mieloide/inmunología , Osteoartritis/patologíaRESUMEN
Fusobacterium nucleatum has been detected in 8%-13% of human colorectal cancer, and shown to inhibit immune responses against primary colorectal tumors in animal models. Thus, we hypothesized that the presence of F. nucleatum might be associated with reduced T cell density in colorectal cancer liver metastases (CRLM). We quantified F. nucleatum DNA in 181 CRLM specimens using quantitative PCR assay. The densities of CD8+ T cells, CD33+ cells (marker for myeloid-derived suppressor cells [MDSCs]), and CD163+ cells (marker for tumor-associated macrophages [TAMs]) in CRLM tissue were determined by immunohistochemical staining. Fusobacterium nucleatum was detected in eight (4.4%) of 181 CRLM specimens. Compared with F. nucleatum-negative CRLM, F. nucleatum-positive CRLM showed significantly lower density of CD8+ T cells (P = .033) and higher density of MDSCs (P = .001). The association of F. nucleatum with the density of TAMs was not statistically significant (P = .70). The presence of F. nucleatum is associated with a lower density of CD8+ T cells and a higher density of MDSCs in CRLM tissue. Upon validation, our findings could provide insights to develop strategies that involve targeting microbiota and immune cells for the prevention and treatment of CRLM.
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Linfocitos T CD8-positivos/citología , Neoplasias Colorrectales/microbiología , Fusobacterium nucleatum/inmunología , Neoplasias Hepáticas/inmunología , Neoplasias Colorrectales/patología , ADN Bacteriano/análisis , Femenino , Fusobacterium nucleatum/genética , Fusobacterium nucleatum/aislamiento & purificación , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/microbiología , Neoplasias Hepáticas/secundario , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Células Supresoras de Origen Mieloide/citología , Macrófagos Asociados a Tumores/citologíaRESUMEN
During chronic infection with Helicobacter pylori, Schlafen 4-expressing myeloid-derived suppressor cells (SLFN4+ MDSCs) create a microenvironment favoring intestinal metaplasia and neoplastic transformation. SLFN4 can be induced by alpha interferon (IFN-α), which is mainly secreted from plasmacytoid dendritic cells (pDCs). This study tested the hypothesis that Helicobacter pylori infection promotes SLFN4+ MDSC differentiation by inducing pDCs to secrete IFN-α. C57BL/6 mice were gavaged with H. pylori, and infection lasted 2, 4, or 6 months. Mouse pDCs were isolated from bone marrow of wild-type C57BL/6J mice. The results showed that H. pylori infection increased the number of SLFN4+ MDSCs by inducing IFN-α expression in mice. Further mechanistic experiments unraveled that IFN-α induced SLFN4 transcription by binding to the Slfn4 promoter. Furthermore, H. pylori infection stimulated pDCs to secrete IFN-α by activating the TLR9-MyD88-IRF7 pathway. Collectively, Helicobacter pylori infection promotes SLFN4+ MDSC differentiation by inducing secretion of IFN-α from pDCs.
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Proteínas Portadoras/genética , Células Dendríticas/inmunología , Infecciones por Helicobacter/inmunología , Helicobacter pylori , Interferón Tipo I/biosíntesis , Células Supresoras de Origen Mieloide/citología , Animales , Diferenciación Celular , Factor 7 Regulador del Interferón/fisiología , Ratones , Ratones Endogámicos C57BL , Factor 88 de Diferenciación Mieloide/fisiología , Regiones Promotoras Genéticas , Receptor Toll-Like 9/fisiologíaRESUMEN
Clinical presentations of COVID-19 are highly variable, yet the precise mechanisms that govern the pathophysiology of different disease courses remain poorly defined. Across the spectrum of disease severity, COVID-19 impairs both innate and adaptive host immune responses by activating innate immune cell recruitment, while resulting in low lymphocyte counts. Recently, several reports have shown that patients with severe COVID-19 exhibit a dysregulated myeloid cell compartment, with increased myeloid-derived suppressor cells (MDSCs) correlating with disease severity. MDSCs, in turn, promote virus survival by suppressing T-cell responses and driving a highly pro-inflammatory state through the secretion of various mediators of immune activation. Here, we summarize the evidence on MDSCs and myeloid cell dysregulation in COVID-19 infection and discuss the potential of MDSCs as biomarkers and therapeutic targets in COVID-19 pneumonia and associated disease.
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COVID-19/patología , Células Supresoras de Origen Mieloide/citología , Células Supresoras de Origen Mieloide/inmunología , SARS-CoV-2/inmunología , Linfocitos T/inmunología , Biomarcadores , Humanos , Inflamación/inmunología , Inflamación/patología , Índice de Severidad de la EnfermedadRESUMEN
Rheumatoid arthritis (RA) is a debilitating autoimmune disease of unknown cause, characterized by infiltration and accumulation of activated immune cells in the synovial joints where cartilage and bone destructions occur. Myeloid-derived suppressor cells (MDSCs) are of myeloid origin and are able to suppress T cell responses. Src homology 2 domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP1) was shown to be involved in the regulation of MDSC differentiation. The purpose of the present study was to investigate the effect of inhibition of SHIP1 on the expansion of MDSCs in RA using a collagen-induced inflammatory arthritis (CIA) mouse model. In DBA/1 mice, treatment with a small molecule-specific SHIP1 inhibitor 3α-aminocholestane (3AC) induced a marked expansion of MDSCs in vivo. Both pretreatment with 3AC of DBA/1 mice prior to CIA induction and intervention with 3AC during CIA progression significantly reduced disease incidence and severity. Adoptive transfer of MDSCs isolated from 3AC-treated mice, but not naïve MDSCs from normal mice, into CIA mice significantly reduced disease incidence and severity, indicating that the 3AC-induced MDSCs were the cellular mediators of the observed amelioration of the disease. In conclusion, inhibition of SHIP1 expands MDSCs in vivo and attenuates development of CIA in mice. Small molecule-specific inhibition of SHIP1 may therefore offer therapeutic benefit to patients with RA and other autoimmune diseases.
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Antiinflamatorios/farmacología , Artritis Experimental/tratamiento farmacológico , Colestanos/farmacología , Células Supresoras de Origen Mieloide/inmunología , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/genética , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Artritis Experimental/genética , Artritis Experimental/inmunología , Artritis Experimental/patología , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Comunicación Celular , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Expresión Génica , Humanos , Cápsula Articular/efectos de los fármacos , Cápsula Articular/inmunología , Cápsula Articular/patología , Ratones , Ratones Endogámicos DBA , Ratones Noqueados , Células Supresoras de Origen Mieloide/citología , Células Supresoras de Origen Mieloide/trasplante , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/antagonistas & inhibidores , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/inmunología , Índice de Severidad de la Enfermedad , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/patologíaRESUMEN
The primary function of myeloid cells is to protect the host from infections. However, during cancer progression or states of chronic inflammation, these cells develop into myeloid-derived suppressor cells (MDSCs) that play a prominent role in suppressing anti-tumor immunity. Overcoming the suppressive effects of MDSCs is a major hurdle in cancer immunotherapy. Therefore, understanding the mechanisms by which MDSCs promote tumor growth is essential for improving current immunotherapies and developing new ones. This review explores mechanisms by which MDSCs suppress T-cell immunity and how this impacts the efficacy of commonly used immunotherapies.
Asunto(s)
Inmunosupresores/uso terapéutico , Inmunoterapia/métodos , Células Supresoras de Origen Mieloide/citología , Neoplasias/inmunología , Neoplasias/terapia , Proliferación Celular , Citocinas/metabolismo , Humanos , Tolerancia Inmunológica , Factores Inmunológicos/farmacología , Terapia de Inmunosupresión , Microbiota , Modelos Biológicos , Células Mieloides , Células Supresoras de Origen Mieloide/patología , Neoplasias/patología , Especies Reactivas de Oxígeno , Microambiente Tumoral/inmunologíaRESUMEN
AIMS: Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The majority of sepsis-related deaths occur during late sepsis, which presents as a state of immunosuppression. Myeloid-derived suppressor cells (MDSCs) have been reported to promote immunosuppression during sepsis. Here we aim to understand the role of microRNAs in regulating MDSCs proliferation and immunosuppression function during sepsis. MAIN METHODS: Murine sepsis model was established using cecal ligation and puncture (CLP). A microarray was used to identify microRNAs with differential expression in murine sepsis. The effect of microRNA-150 on MDSCs proliferation and function was then evaluated. 140 multiple trauma patients from Tongji Hospital and 10 healthy controls were recruited. Peripheral blood samples were taken and the serum level of miR-150 was measured. KEY FINDINGS: In the murine model of sepsis, MDSCs expansion was noted in the spleen and bone marrow, while expression of miR-150 in MDSCs decreased. Replenishing miR-150 inhibited the expansion of MDSCs in both monocytic and polymorphonuclear subpopulations, as well as decreasing the immunosuppressive function of MDSCs, through down-regulation of ARG1. Both pro-inflammatory cytokine IL-6 and anti-inflammatory cytokines TGF-ß and IL-10 were reduced by miR-150. In human, the serum level of miR-150 was down-regulated in septic patients and elevated in non-septic trauma patients compared to healthy controls. SIGNIFICANCE: Our study showed that MiR-150 is down-regulated during sepsis. Replenishing miR-150 reduces the immunosuppression function of MDSCs by down-regulating ARG1 in late sepsis. MiR-150 might serve as a potential therapeutic option for sepsis.
Asunto(s)
Arginasa/metabolismo , Proliferación Celular , MicroARNs/genética , Células Supresoras de Origen Mieloide/inmunología , Sepsis/patología , Adolescente , Adulto , Anciano , Animales , Arginasa/genética , Estudios de Casos y Controles , Citocinas/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Tolerancia Inmunológica/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Células Supresoras de Origen Mieloide/citología , Sepsis/genética , Sepsis/inmunología , Sepsis/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Patients are susceptible to immunosuppression in late-stage of sepsis, in which myeloid-derived suppressor cells (MDSCs) is an important contributor. This study aims to investigate whether all-trans-retinoic acid (ATRA), which has been proved to inhibit MDSCs generation in cancer, will ameliorate sepsis-induced immuno-suppression through modulating MDSCs. METHODS: A clinically relevant "two-hit'' model of sepsis, the cecal ligation and puncture (CLP) model and secondary pneumonia model, were established in mice. The effects of ATRA on the mortality, the bacterial burden, the expansion and activity of CLP-induced MDSCs, as well as the function of CD4+ T cells were evaluated. RESULTS: In CLP model, ATRA was found to reduce frequency of MDSCs in spleen of mice and inhibit activity of MDSCs by regulating the generation and activity of arginase-1 and iNOS, and the secretion of immune-supressive cytokines. ATRA administration eventually reduced mortality of secondary infection by Legionella pneumophila in CLP-surviving mice, which might be associated with the restoration of CD4+ T cells proliferating and secreting activity. CONCLUSION: ATRA can restore CD4+ T cells dysfunction in sepsis by modulating the expansion and function of MDSCs and therefore provides a potential therapy that targets the immunosuppressive state of sepsis.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Legionella pneumophila/inmunología , Células Supresoras de Origen Mieloide/inmunología , Sepsis/inmunología , Tretinoina/farmacología , Animales , Arginasa/metabolismo , Citocinas/metabolismo , Enfermedad de los Legionarios/inmunología , Enfermedad de los Legionarios/mortalidad , Ratones , Ratones Endogámicos C57BL , Células Supresoras de Origen Mieloide/citología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Sepsis/microbiología , Sepsis/patologíaRESUMEN
Cheng and colleagues reported previously unexplored correlations between circulating levels of immune cells and biomarkers and bone regeneration, which served as support for the construction of a model ensemble that can predict bone regeneration. If validated in humans, this tool could be valuable in the management of non-union fractures.