Efferocytosis Fuels Requirements of Fatty Acid Oxidation and the Electron Transport Chain to Polarize Macrophages for Tissue Repair
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA498080 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8097407_1.fastq.gz | Fastqsanger.gz | |||
| SRR8097407_2.fastq.gz | Fastqsanger.gz | |||
| SRR8097408_1.fastq.gz | Fastqsanger.gz | |||
| SRR8097408_2.fastq.gz | Fastqsanger.gz | |||
| SRR8097409_1.fastq.gz | Fastqsanger.gz |
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Project description:Efferocytosis fuels malignant pleural effusion through TIMP1
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Project description:During wound injury, efferocytosis fills the macrophage with a metabolite load nearly equal to the phagocyte itself. A timely question pertains to how metabolic phagocytic signaling regulates the signature anti-inflammatory macrophage response. Here we report the metabolome of activated macrophages during efferocytosis to reveal an interleukin-10 (IL-10) cytokine escalation that was independent of glycolysis yet bolstered by apoptotic cell fatty acids and mitochondrial β-oxidation, the electron transport chain, and heightened coenzyme NAD+. Loss of IL-10 due to mitochondrial complex III defects was remarkably rescued by adding NAD+ precursors. This activated a SIRTUIN1 signaling cascade, largely independent of ATP, that culminated in activation of IL-10 transcription factor PBX1. Il-10 activation by the respiratory chain was also important in vivo, as efferocyte mitochondrial dysfunction led to cardiac rupture after myocardial injury. These findings highlight a new paradigm whereby macrophages leverage efferocytic metabolites and electron transport for anti-inflammatory reprogramming that culminates in organ repair.
| S-EPMC6471613 | biostudies-literature
Project description:Malignant Pleural Effusion (MPE) results from the capacity of several human cancers to metastasize to the pleural cavity. The median survival is 3-12 months and no effective treatments are currently available. Immune-based therapies have failed until now, reflecting our insufficient understanding of the basic immunological mechanisms leading to MPE progression. Here, we show that phagocytosis of apoptotic cells in the pleural cavity fuels the progression of MPE. We found that efferocytosis through the receptor tyrosine kinases AXL and MERTK in macrophages led to the production of IL-10. Using single cell RNA-Seq, we revealed that IL-10 is indeed produced by four distinct pleural cavity macrophage subpopulations characterized by different metabolic states and cell chemotaxis properties. In turn, IL-10 acts on dendritic cells (DCs) inducing the production of tissue inhibitor of metalloproteinases 1 (TIMP1). Genetic ablation of AXL and MERTK in macrophages or IL-10 receptor in DCs or TIMP1 significantly reduced MPE progression. Taken together, our results delineate an inflammatory cascade – from the clearance of apoptotic cells by macrophages, to production of IL-10, to induction of TIMP1 in DCs – that facilitates MPE progression. This inflammatory cascade offers a series of targets for therapies which aim at preventing or treating MPE.
2021-08-24 | GSE172455 | GEO
Project description:Sustained smouldering, or low grade, activation of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis. Distinct metabolic and mitochondrial features of myeloid cells guide diverse functional states. How these features act to perpetuate neuroinflammation is currently unknown. Using a multiomics approach, we identify a new molecular signature that perpetuates the activation of microglia by the reverse electron transport through complex I and the subsequent production of reactive oxygen species. Blocking reverse electron transport in pro-inflammatory myeloid cells protects against neurotoxic damage and improves functional outcomes in animal disease models in vivo. Our data show that reverse electron transport in myeloid cells is a potential new therapeutic target to foster neuroprotection in smouldering inflammatory central nervous system diseases.
2025-01-31 | GSE224366 | GEO
Project description:Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of Complex I (CI) and II (CII), the gatekeepers for initiating electron flow, remains unclear. Here, we report that loss of CII, but not CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex I-antigen processing and presentation (MHC-APP) genes that is independent of interferon signaling. Furthermore, knock-out of MCJ, to promote electron entry preferentially via CI, provides proof-of-concept of ETC rewiring to achieve anti-tumor responses without side effects associated with an overall reduction in mitochondrial respiration in non-cancer cells. Our results hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.
2024-05-01 | GSE235311 | GEO
Project description:Inflammation is a physiopathological process triggered by infection or tissue damage. Immune system initiates coordinated sequential steps in response to these danger signals. Once the threat has been contained inflammation has to be subsequently shut down. Inflammation resolution is initiated by the reprogramming of pro-inflammatory macrophages toward a pro-resolving profile. This reprogramming is induced in particular by the non-phlogistic engulfment of apoptotic cells, mostly apoptotic neutrophils, a process called efferocytosis. As a matter of fact, macrophages are an essential linchpin regulating both inflammation triggering and sustaining and inflammation resolution. This duality can be achieved through the tremendous plasticity of these innate immune cells. Indeed, depending on microenvironmental signals (cytokines, efferocytosis, growth factors…) macrophages can adopt numerous diverse and sometimes antagonistic phenotypes. The mechanisms governing these transitions remain relatively scattered especially in human. With this project we propose to explore the mechanisms involved in human macrophage reprogramming toward a pro-resolving profile after efferocytosis. The stakes are high due to the estimated prevalence of chronic inflammatory diseases in Western society is 5 to 7%. Chronic inflammation is a burden to patient due to life-long debilitating illness and increased mortality and is also a burden to society due to high costs for therapy and care. Finding new therapies to limit chronic inflammation establishment and persistence is thus a highly valuable goal.
2021-12-01 | E-MTAB-8885 | biostudies-arrayexpress
Project description:The phagocytic clearance of apoptotic cells, termed efferocytosis, is essential for both tissue homeostasis and tissue health during cell death-inducing treatments. Failure to efficiently clear apoptotic cells augment the risk of pathological inflammation and has been linked to a myriad of autoimmune and inflammatory diseases. Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis in a tissue, whether signals arising distally also regulate homeostatic efferocytosis remains elusive. Interestingly, clinical evidence suggests that prolonged use of broad-spectrum antibiotics is associated with an increased risk of autoimmune and inflammatory disease development. We therefore hypothesized that intestinal microbes produce molecular signals that regulate efferocytotic ability in tissue phagocytes beyond the intestines. Here, we find that macrophages, the body’s professional phagocyte, display impaired efferocytosis in the peritoneum of broad-spectrum antibiotics (ABX)-treated, vancomycin-treated, and germ-free mice in vivo, the latter of which could be rescued by fecal microbiota transplantation. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosted efferocytosis efficiency and capacity in mouse and human macrophages, with both intestinal and local delivery of butyrate capable of rescuing ABX-induced large peritoneal macrophage (LPM) efferocytosis defects. Bulk mRNA sequencing of butyrate-treated primary macrophages in vitro and single cell mRNA sequencing of LPMs isolated from ABX-treated and butyrate-rescued mice revealed specific regulation of efferocytosis-supportive transcriptional programs. Specifically, we found that the efferocytosis receptor T-cell immunoglobulin and mucin domain containing 4 (TIM-4, Timd4) was downregulated in LPMs of ABX-treated mice which was rescued by oral butyrate and that TIM-4 was required for the butyrate-induced enhancement of LPM efferocytosis capacity in vivo. Strikingly, LPM efferocytosis was impaired well-beyond withdrawal of ABX and, importantly, ABX-treated mice exhibited significantly worse disease in a mouse model of system lupus erythematosus. Collectively, our results demonstrate that homeostatic efferocytosis relies on distal molecular signals and suggest that a defect in homeostatic efferocytosis may contribute to the clinically observed link between broad-spectrum antibiotics use and inflammatory disease.
2025-06-24 | GSE270751 | GEO