ABSTRACT
Tight control of inflammatory gene expression by antagonistic environmental cues is key to ensure immune protection while preventing tissue damage. Prostaglandin E2 (PGE2) modulates macrophage activation during homeostasis and disease, but the underlying mechanisms remain incompletely characterized. Here we dissected the genomic properties of lipopolysaccharide (LPS)-induced genes whose expression is antagonized by PGE2. The latter molecule targeted a set of inflammatory gene enhancers that, already in unstimulated macrophages, displayed poorly permissive chromatin organization and were marked by the transcription factor myocyte enhancer factor 2A (MEF2A). Deletion of MEF2A phenocopied PGE2 treatment and abolished type I interferon (IFN I) induction upon exposure to innate immune stimuli. Mechanistically, PGE2 interfered with LPS-mediated activation of ERK5, a known transcriptional partner of MEF2. This study highlights principles of plasticity and adaptation in cells exposed to a complex environment and uncovers a transcriptional circuit for IFN I induction with relevance for infectious diseases or cancer.
Subject(s)
Dinoprostone/immunology , Interferon Type I/immunology , Macrophage Activation/immunology , Macrophages/immunology , Animals , Cell Line , Cells, Cultured , Gene Expression Regulation/immunology , Humans , Inflammation/genetics , Inflammation/immunology , Interferon Type I/biosynthesis , Lipopolysaccharides , MEF2 Transcription Factors/genetics , MEF2 Transcription Factors/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitogen-Activated Protein Kinase 7/metabolismABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapies1. Inflammatory and immunomodulatory signals co-exist in the pancreatic tumour microenvironment, leading to dysregulated repair and cytotoxic responses. Tumour-associated macrophages (TAMs) have key roles in PDAC2, but their diversity has prevented therapeutic exploitation. Here we combined single-cell and spatial genomics with functional experiments to unravel macrophage functions in pancreatic cancer. We uncovered an inflammatory loop between tumour cells and interleukin-1ß (IL-1ß)-expressing TAMs, a subset of macrophages elicited by a local synergy between prostaglandin E2 (PGE2) and tumour necrosis factor (TNF). Physical proximity with IL-1ß+ TAMs was associated with inflammatory reprogramming and acquisition of pathogenic properties by a subset of PDAC cells. This occurrence was an early event in pancreatic tumorigenesis and led to persistent transcriptional changes associated with disease progression and poor outcomes for patients. Blocking PGE2 or IL-1ß activity elicited TAM reprogramming and antagonized tumour cell-intrinsic and -extrinsic inflammation, leading to PDAC control in vivo. Targeting the PGE2-IL-1ß axis may enable preventive or therapeutic strategies for reprogramming of immune dynamics in pancreatic cancer.
Subject(s)
Inflammation , Interleukin-1beta , Pancreatic Neoplasms , Tumor-Associated Macrophages , Humans , Carcinogenesis , Carcinoma, Pancreatic Ductal/complications , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/pathology , Dinoprostone/metabolism , Disease Progression , Gene Expression Regulation, Neoplastic , Inflammation/complications , Inflammation/immunology , Inflammation/pathology , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , Pancreatic Neoplasms/complications , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , Tumor Microenvironment , Tumor Necrosis Factors/metabolism , Tumor-Associated Macrophages/immunology , Tumor-Associated Macrophages/metabolism , Tumor-Associated Macrophages/pathologyABSTRACT
99mTc-based radiopharmaceuticals are the most commonly used medical radioactive tracers in nuclear medicine for diagnostic imaging. Due to the expected global shortage of 99Mo, the parent radionuclide from which 99mTc is produced, new production methods should be developed. The SORGENTINA-RF (SRF) project aims at developing a prototypical medium-intensity D-T 14-MeV fusion neutron source specifically designed for production of medical radioisotopes with a focus on 99Mo. The scope of this work was to develop an efficient, cost-effective and green procedure for dissolution of solid molybdenum in hydrogen peroxide solutions compatible for 99mTc production via the SRF neutron source. The dissolution process was extensively studied for two different target geometries: pellets and powder. The first showed better characteristics and properties for the dissolution procedure, and up to 100 g of pellets were successfully dissolved in 250-280 min. The dissolution mechanism on the pellets was investigated by means of scanning electron microscopy and energy-dispersive X-ray spectroscopy. After the procedure, sodium molybdate crystals were characterized via X-ray diffraction, Raman and infrared spectroscopy and the high purity of the compound was established by means of inductively coupled plasma mass spectroscopy. The study confirmed the feasibility of the procedure for production of 99mTc in SRF as it is very cost-effective, with minimal consumption of peroxide and controlled low temperature.
ABSTRACT
Na2MoO4 and Na2WO4 are isostructural semiconductors, belonging to the spinel class. They have interesting properties and find applications in numerous sectors. These properties can be tuned by controlling the composition of their solid solutions. Here, different methods to obtain these compounds are presented, both wet and solid-state synthesis. The obtained results show a possible dependence of the material properties on the chosen synthesis method. The pure compounds and their mixtures were characterized by Raman spectroscopy, scanning electron microscopy, and X-ray diffraction.