RESUMO
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.
Assuntos
Dinoprostona/imunologia , Interferon Tipo I/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Animais , Linhagem Celular , Células Cultivadas , Regulação da Expressão Gênica/imunologia , Humanos , Inflamação/genética , Inflamação/imunologia , Interferon Tipo I/biossíntese , Lipopolissacarídeos , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 7 Ativada por Mitógeno/metabolismoRESUMO
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.
Assuntos
Inflamação , Interleucina-1beta , Neoplasias Pancreáticas , Macrófagos Associados a Tumor , Humanos , Carcinogênese , Carcinoma Ductal Pancreático/complicações , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Dinoprostona/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Inflamação/complicações , Inflamação/imunologia , Inflamação/patologia , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Microambiente Tumoral , Fatores de Necrose Tumoral/metabolismo , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologiaRESUMO
Most, if not all, aspects of carcinogenesis are influenced by the tumor microenvironment (TME), a complex architecture of cells, matrix components, soluble signals, and their dynamic interactions in the context of physical traits of the tissue. Expanding application of technologies for high-dimensional analyses with single-cell resolution has begun to decipher the contributions of the immune system to cancer progression and its implications for therapy. In this review, we will discuss the multifaceted roles of tumor-associated macrophages and neutrophils, focusing on factors that subvert tissue immune homeostasis and offer therapeutic opportunities for TME reprogramming. By performing a critical analysis of available datasets, we elaborate on diversification mechanisms and unifying principles of myeloid cell heterogeneity in human tumors.