Hif1α Deletion Limits Tissue Regeneration via Aberrant B Cell Accumulation in Experimental Pancreatitis

Lee, Kyoung Eun; Spata, Michelle; Maduka, Richard C.; Vonderheide, Robert H.; Simon, M. Celeste

doi:10.1016/j.celrep.2018.05.071

Cited by 12 publications

(8 citation statements)

References 33 publications

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“… 59 A recent study with an experimental CP model suggests a pathogenic role for B cells in tissue regeneration. 60 Our scRNA-seq analysis revealed significantly increased frequencies of B cells and plasma cells in both CP groups, with differential gene expression signatures between hereditary and idiopathic CP ( online supplemental figure 12A, B ). These data implicate B cells, along with other immune subsets, in the immunopathogenic mechanisms of CP and requires future investigation.…”

Section: Discussionmentioning

confidence: 82%

Single-cell sequencing unveils distinct immune microenvironments with CCR6-CCL20 crosstalk in human chronic pancreatitis

Namkoong

Yang

Huang

et al. 2021

Gut

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ObjectiveChronic pancreatitis (CP) is a potentially fatal disease of the exocrine pancreas, with no specific or effective approved therapies. Due to difficulty in accessing pancreas tissues, little is known about local immune responses or pathogenesis in human CP. We sought to characterise pancreatic immune responses using tissues derived from patients with different aetiologies of CP and non-CP organ donors in order to identify key signalling molecules associated with human CP.DesignWe performed single-cell level cellular indexing of transcriptomes and epitopes by sequencing and T-cell receptor (TCR) sequencing of pancreatic immune cells isolated from organ donors, hereditary and idiopathic patients with CP who underwent total pancreatectomy. We validated gene expression data by performing flow cytometry and functional assays in a second patient with CP cohort.ResultsDeep single-cell sequencing revealed distinct immune characteristics and significantly enriched CCR6+ CD4+ T cells in hereditary compared with idiopathic CP. In hereditary CP, a reduction in T-cell clonality was observed due to the increased CD4+ T (Th) cells that replaced tissue-resident CD8+ T cells. Shared TCR clonotype analysis among T-cell lineages also unveiled unique interactions between CCR6+ Th and Th1 subsets, and TCR clustering analysis showed unique common antigen binding motifs in hereditary CP. In addition, we observed a significant upregulation of the CCR6 ligand (CCL20) expression among monocytes in hereditary CP as compared with those in idiopathic CP. The functional significance of CCR6 expression in CD4+ T cells was confirmed by flow cytometry and chemotaxis assay.ConclusionSingle-cell sequencing with pancreatic immune cells in human CP highlights pancreas-specific immune crosstalk through the CCR6-CCL20 axis, a signalling pathway that might be leveraged as a potential future target in human hereditary CP.

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Section: Discussionmentioning

confidence: 82%

Single-cell sequencing unveils distinct immune microenvironments with CCR6-CCL20 crosstalk in human chronic pancreatitis

Namkoong

Yang

Huang

et al. 2021

Gut

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“…AMPK, a sensor of intracellular energy, can be activated at low energy levels and regulate cellular processes . SAP, an inflammatory disease of the exocrine pancreas, induces tissue hypoxia . GSEA indicated that HALLMARK_HYPOXIA was significantly up-regulated in SAP (SI Table S8).…”

Section: Discussionmentioning

confidence: 99%

“…38 SAP, an inflammatory disease of the exocrine pancreas, induces tissue hypoxia. 39 GSEA indicated that HALLMARK_HYPOXIA was significantly up-regulated in SAP (SI Table S8). Hypoxia induces oxidative stress, which is an important signal in cellular injury and plays a crucial role in the pathogenesis of SAP.…”

Section: ■ Discussionmentioning

confidence: 99%

Improved Integrated Whole Proteomic and Phosphoproteomic Profiles of Severe Acute Pancreatitis

et al. 2020

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Severe acute pancreatitis (SAP) is caused by complicated biological factors, and revealing its complex pathogenesis by single-target analysis is difficult. Systematic studies have developed slowly because extraction of degradable pancreatic proteins exposed to multiple proteases is challenging. We present integrated whole proteomic and phosphoproteomic profiles of SAP rats based on a modified protein extraction strategy with less protein degradation. Data-dependent acquisition (DDA) and data-independent acquisition (DIA) strategies were applied to select an appropriate method. Total 275 differentially expressed proteins and 757 differentially expressed phosphorylated proteins were identified by DIA-based quantitative proteomics. Several signal transduction pathways, including the AMPK, MAPK, and PI3K-Akt pathways, were enriched in SAP. Up-regulation of phosphorylated proteins involved in the process of TNFA signaling and inflammatory response was also detected in SAP. Our results improve the understanding of SAP development and progression.

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“…276 Depletion of B cells increases exocrine tissue regeneration owing to a significant decrease in overall immune infiltrations and fibrosis. 277 Pancreatitis-induced tissue hypoxia and HIF-1α accumulation-induced B-cell depletion enhances pancreatic regeneration. B cell depletion in mice with pancreatitis significantly enhanced tissue regeneration and chemotherapeutic drug resistance.…”

Section: Hypoxia and Angiogenesismentioning

confidence: 99%

Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions

Zhou

Han

et al. 2023

Sig Transduct Target Ther

240

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Having a hypoxic microenvironment is a common and salient feature of most solid tumors. Hypoxia has a profound effect on the biological behavior and malignant phenotype of cancer cells, mediates the effects of cancer chemotherapy, radiotherapy, and immunotherapy through complex mechanisms, and is closely associated with poor prognosis in various cancer patients. Accumulating studies have demonstrated that through normalization of the tumor vasculature, nanoparticle carriers and biocarriers can effectively increase the oxygen concentration in the tumor microenvironment, improve drug delivery and the efficacy of radiotherapy. They also increase infiltration of innate and adaptive anti-tumor immune cells to enhance the efficacy of immunotherapy. Furthermore, drugs targeting key genes associated with hypoxia, including hypoxia tracers, hypoxia-activated prodrugs, and drugs targeting hypoxia-inducible factors and downstream targets, can be used for visualization and quantitative analysis of tumor hypoxia and antitumor activity. However, the relationship between hypoxia and cancer is an area of research that requires further exploration. Here, we investigated the potential factors in the development of hypoxia in cancer, changes in signaling pathways that occur in cancer cells to adapt to hypoxic environments, the mechanisms of hypoxia-induced cancer immune tolerance, chemotherapeutic tolerance, and enhanced radiation tolerance, as well as the insights and applications of hypoxia in cancer therapy.

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Hif1α Deletion Limits Tissue Regeneration via Aberrant B Cell Accumulation in Experimental Pancreatitis

Cited by 12 publications

References 33 publications

Single-cell sequencing unveils distinct immune microenvironments with CCR6-CCL20 crosstalk in human chronic pancreatitis

Single-cell sequencing unveils distinct immune microenvironments with CCR6-CCL20 crosstalk in human chronic pancreatitis

Improved Integrated Whole Proteomic and Phosphoproteomic Profiles of Severe Acute Pancreatitis

Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions

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