Stat3 and C/EBPβ synergize to induce miR‐21 and miR‐181b expression during sepsis

McClure, Clara; McPeak, Melissa B.; Youssef, Dima; Yao, Zhi Q.; McCall, Charles E.; Gazzar, Mohamed El

doi:10.1038/icb.2016.63

Cited by 56 publications

(71 citation statements)

References 59 publications

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“…We also reported that C/EBPα, and not C/EBPβ, binds the same consensus motif at miR-21 and miR-181b promoters and is required for generating immune competent Gr1 + CD11b + cells (McClure et al , 2017), thus disrupting expression of miR-21 and miR-181b. In this study and using Chromatin immunoprecipitation (ChIP) assay, we show that C/EBPβ binding at the miR-21 promoter in sepsis but not sham Gr1 + CD11b + cells from the control mice, which further increased in late sepsis cells (Fig.…”

Section: Resultsmentioning

confidence: 87%

“…Morever, mice with C/EBPβ conditional knockout survive late sepsis and generate Gr1 + CD11b + immune competent myeloid progenitors (McPeak et al , 2017). C/EBPβ induces miR-21 and miR-181b to generate immunosuppressive Gr1 + CD11b + in the bone marrow of septic mice (McClure et al , 2017). In this study, we hypothesized that genetic deletion Cebpb will disrupt the path that leads to Gr1 + CD11b + MDSC generation.…”

Section: Resultsmentioning

confidence: 99%

“…We previously reported that C/EBPβ plays an essential and proximal role in generating immunosuppressive Gr1 + CD11b + myeloid cells (McClure et al , 2017; McPeak et al , 2017). Taking a genetic approach, we confirm and extend support of the concept that C/EBPβ epigenetically controls miR-21 and miR-181b expression to drive MDSC reprogramming to the repressor phenotype so important in sepsis outcome.…”

Section: Discussionmentioning

confidence: 99%

“…Enrichment of the miR-21 and miR-181b promoter sequences in the ChIPed DNA was measured by quantitative real-time PCR using primer and fluorescently labeled internal probe sequences (Integrated DNA Technologies, Coralville, IA) specific to the miR-21 and miR-181b promoters, as described previously (McClure et al , 2017). …”

Section: Methodsmentioning

confidence: 99%

“…We previously reported that C/EBPβ in conjunction with Stat3 binds to and activates the promoters of both miR-21 and miR-181b in naive Gr1 + CD11b + cells (McClure et al , 2017), which are phenotypically similar to MDSCs. We hypothesized that C/EBPβ triggers the miR-21 and miR-181b dependent path that generates MDSCs during late sepsis immunosuppression.…”

Section: Introductionmentioning

confidence: 99%

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Expression of C/EBPβ in myeloid progenitors during sepsis promotes immunosuppression

Dai

Kumbhare

Youssef

et al. 2017

Molecular Immunology

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Sepsis-induced myeloid-derived suppressor cells (MDSCs) contribute to immunosuppression associated with sepsis. We reported that the CCAAT enhancer-binding protein C/EBPβ activates microRNA (miR)-21 and miR-181b expressions, which induce transcription factor NFI-A to support the generation and expansion of MDSCs in the bone marrow and spleens of septic mice. Here, using a conditional knockout mouse model lacking C/EBPβ in the myeloid lineage, we find that without C/EBPβ, myeloid progenitor cells could not express miR-21 or miR-181b, and ectopic expression of C/EBPβ in the C/EBPβ-deficient myeloid progenitors activated the expression of the two miRNAs. Moreover, C/EBPβ-reconstituted myeloid cells expressed IL-10 and reduced T cell proliferation and function, similar to control MDSCs that express C/EBPβ. Exogenous expression of miR-21 and miR-181b in the C/EBPβ-deficient myeloid progenitors from septic mice produced similar results. Notably, NFI-A-dependent transactivation of NF-kB MDSC generating pathway was reversed in the C/EBPβ-deficient myeloid progenitors from septic mice. Together, these results support that decreasing C/EBPβ expression prevents MDSC generation and decreases immunosuppression in septic mice, providing a target for sepsis treatment.

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Section: Resultsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expression of C/EBPβ in myeloid progenitors during sepsis promotes immunosuppression

Dai

Kumbhare

Youssef

et al. 2017

Molecular Immunology

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Tumor‐associated neutrophils (TANs) in human carcinoma‐draining lymph nodes: a novel TAN compartment

et al. 2021

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Objectives The role of tumor‐associated neutrophils (TANs) in the nodal spread of cancer cells remains unexplored. The present study evaluates the occurrence and clinical significance of human nodal TANs. Methods The relevance, derivation, phenotype and interactions of nodal TANs were explored via a large immunohistochemical analysis of carcinoma‐draining lymph nodes, and their clinical significance was evaluated on a retrospective cohort of oral squamous cell carcinomas (OSCC). The tumor‐promoting function of nodal TAN was probed in the OSCC TCGA dataset combining TAN and epithelial‐to‐mesenchymal transition (EMT) signatures. Results The pan‐carcinoma screening identified a consistent infiltration (59%) of CD66b+ TANs in tumor‐draining lymph nodes (TDLNs). Microscopic findings, including the occurrence of intra‐lymphatic conjugates of TANs and cancer cells, indicate that TANs migrate through lymphatic vessels. In vitro experiments revealed that OSCC cell lines sustain neutrophil viability and activation via release of GM‐CSF. Moreover, by retrospective analysis, a high CD66b+ TAN density in M‐TDLNs of OSCC (n = 182 patients) predicted a worse prognosis. The analysis of the OSCC‐TCGA dataset unveiled that the expression of a set of neutrophil‐specific genes in the primary tumor (PT) is highly associated with an EMT signature, which predicts nodal spread. Accordingly, in the PT of OSCC cases, CD66b+TANs co‐localised with PDPN+S100A9− EMT‐switched tumor cells in areas of lymphangiogenesis. The pro‐EMT signature is lacking in peripheral blood neutrophils from OSCC patients, suggesting tissue skewing of TANs. Conclusion Our findings are consistent with a novel pro‐tumoral TAN compartment that may promote nodal spread via EMT, through the lymphatics.

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Myeloid‐derived suppressor cells: Roles in the tumor microenvironment and tumor radiotherapy

Yin

Wang

et al. 2018

Intl Journal of Cancer

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Cancer progression is closely related to the tumor microenvironment in which the tumor exists, including surrounding blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, signaling molecules and the extracellular matrix. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can impact the growth and evolution of cancerous cells. One of major cell components in the tumor microenvironment is myeloid-derived suppressor cells (MDSCs), which promote tumor growth and metastasis directly or indirectly by recognizing other immune cells, producing cytokines and exerting their immunosuppression functions. MDSCs have emerged as major regulators of immune responses in cancer and key targets for treating cancer. There are many limitations and side-effect in approaches of conventional cancer therapy, including radiotherapy. It has grown up to be a burgeoning field that a combination of radiotherapy and immunotherapy applied to cancer therapy. Therefore, it is fundamental to explore the immune mechanism in the process of cancer treatment. Here, we reviewed the recent progress of MDSCs in roles of the tumor microenvironment and tumor radiotherapy.

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Stat3 and C/EBPβ synergize to induce miR‐21 and miR‐181b expression during sepsis

Cited by 56 publications

References 59 publications

Expression of C/EBPβ in myeloid progenitors during sepsis promotes immunosuppression

Expression of C/EBPβ in myeloid progenitors during sepsis promotes immunosuppression

Tumor‐associated neutrophils (TANs) in human carcinoma‐draining lymph nodes: a novel TAN compartment

Myeloid‐derived suppressor cells: Roles in the tumor microenvironment and tumor radiotherapy

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