Efferocytosis induces proangiogenic function and chromatin remodeling in tumor-associated macrophages
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE300757 | GEO | 2026/06/05
REPOSITORIES: GEO
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Project description:Macrophages remove apoptotic cells by efferocytosis during immune-surveillance and in the tumor microenvironment (TME). However, the gradual molecular and epigenetic consequences of efferocytosis on the single macrophage are not thoroughly elucidated. Here we introduce Effero-seq, an approach that captures single-cell transcriptomic changes coupled with lysosomal acidification tracked by pHrodo, thus enabling the dissection of molecular dynamics over time following engulfment. Using apoptotic pHrodo-labeled cells as cargo, we defined the effero-score, a gene program gradually upregulated correlatively with pHrodo intensity. In a murine melanoma model, we found that efferocytosis induces a pro-angiogenic function in macrophages with spatial proximity to vascular niches. Moreover, efferocytosis reprograms chromatin accessibility, leading to attenuated macrophage response to IFNγ. In human uveal melanoma, expression of the effero-score is correlated with poor survival. Effero-seq sheds light on the molecular reprogramming induced by efferocytosis in the TME, opening new avenues for understanding macrophage function and developing targeted treatments.
2026-06-05 | GSE306916 | GEO
Project description:Efficient clearance and degradation of apoptotic cardiomyocytes by macrophages (termed efferocytosis) are critical for inflammation resolution and restoration of cardiac function after myocardial ischemia/reperfusion (I/R). Here, we define secreted and transmembrane protein 1a (Sectm1a), a cardiac macrophage-enriched gene, as a modulator of macrophage efferocytosis in I/R hearts. Upon myocardial I/R, Sectm1a-KO mice exhibit impaired macrophage efferocytosis, leading to massive accumulation of apoptotic cardiomyocytes, cardiac inflammation, fibrosis, and consequently, exaggerated cardiac dysfunction. By contrast, therapeutic administration of recombinant SECTM1A protein significantly enhances macrophage efferocytosis and improves cardiac function. Mechanistically, SECTM1A can elicit autocrine effects on the activation of glucocorticoid-induced TNF receptor (GITR) at the surface of macrophages, leading to the upregulation of liver X receptor alpha (LXRα) and its downstream efferocytosis-related genes and lysosomal enzyme genes. Our study suggests that Sectm1a-mediated activation of Gitr/LXRα axis could be a promising approach to enhance macrophage efferocytosis for the treatment of myocardial I/R injury.
2024-01-23 | GSE253579 | GEO
Project description:Macrophage efferocytosis, the clearance of apoptotic cells, is essential for tissue homeostasis and preventing inflammation. Impaired efferocytosis contributes to chronic inflammatory conditions, including obesity. However, its key regulators remain unclear. MicroRNA-130b (miR-130b) is increased in adipose tissue macrophages of individuals with obesity. Here, we found that miR-130b was enriched in bone marrow of mice, and its expression in bone marrow-derived macrophages was suppressed by IL-4 and by apoptotic cell uptake. Deletion of the miR-130b and its cluster member miR-301b enhanced macrophage efferocytosis in vitro and apoptotic cell clearance in vivo, accompanied by increased mitochondrial respiration and anti-inflammatory polarization. In high-fat diet-fed mice, global deletion of miR-130b/301b reduced inflammatory gene expression in adipose tissues. Mechanistically, miR-130b suppressed PPARγ and PGC-1α, regulators of mitochondrial metabolism and inflammation, and miR-130b/301b deletion increased CX3CR1, a receptor for apoptotic cell “find me” signals. Together, miR-130b/301b deletion promotes macrophage efferocytosis and resolves adipose tissue inflammation.
2026-03-02 | GSE312838 | GEO
Project description:Fever, a cardinal sign of inflammation, has been shown to modulate macrophage functions. Here, we wonder whether fever affects macrophage efferocytosis. This process is critical for the resolution of inflammation and the return to homeostasis with the reprogramming of macrophages toward a pro-resolving phenotype. Using primary mouse bone marrow-derived macrophages (BMDM) stimulated by LPS and IFN-γ (M1-like BMDM), we first validated that exposure to febrile-range temperature (39.5°C) induced a heat shock protein response. This was done by RNA sequencing (RNAseq), quantitative RT-PCR (RT-qPCR), and intracellular flow cytometry (FC). Then, we observed that febrile-range temperature decreased pro-inflammatory macrophage efferocytosis assessed by two different FC-based assays and by IncuCyte® live-cell imaging. This reduced efferocytic capacity of macrophages exposed to febrile-range temperature resulted from a decrease capacity to interact with apoptotic cells and to internalise these dying cells. This real-time image-based efferocytosis assay showed also that the heat reduced cell motility of macrophages in response to apoptotic cells. In our RNAseq dataset, we found an upregulation of the Adam17 gene and confirmed this increase by RT-qPCR analysis. Since this gene encodes a protease shedding the efferocytic receptor Mer, we determined Mer expression by FC and soluble Mer in the culture supernatants by ELISA. Febrile-range hyperthermia induced the cleavage of Mer from the cell surface of pro-inflammatory macrophages. Overall, decreased efferocytosis induced by fever-range hyperthermia may result from reduced Mer expression. This suggests that fever, by acting on Mer expression, decreases the efferocytic capacity of macrophages to prolong the pro-inflammatory state.
2025-12-19 | E-MTAB-14408 | biostudies-arrayexpress
Project description:Defects in apoptotic cell clearance, or efferocytosis, can cause inflammatory diseases and prevent tissue repair due in part, to a key role of efferocytosis in inducing a pro-repair transcriptional program in phagocytic cells like macrophages. While the cellular machinery and metabolic pathways involved in efferocytosis have been characterized, the precise efferocytic response of macrophages is dependent on the identity and macromolecular cues of apoptotic cells, and the complex tissue microenvironment in which efferocytosis occurs. Here, we find that macrophages undergoing active efferocytosis in mid-stage mouse skin wounds in vivo display a pro-repair gene program, while efferocytosis of apoptotic skin fibroblasts in vitro induces an immature/inflammatory transcription response. These data provide a resource for understanding how the skin wound niche influences macrophage efferocytosis and will be useful for future investigations that define the role of efferocytosis during tissue repair
2024-08-06 | GSE273754 | GEO
Project description:In response to organ injury in adults, macrophages often promote scarring, yet during early life are required for tissue regeneration. To elucidate mechanisms underlying age-associated regeneration, we compared the macrophage injury response in newborns versus adult hearts. Single cell analysis revealed an accumulation of tissue-resident macrophages in neonates that were selectively polarized for apoptotic cell recognition and uptake (efferocytosis). Ablation of the apoptotic cell recognition receptor Mertk in newborns prevented cardiac regeneration. These findings could be attributed to reprogramming of macrophage gene expression that was required for biosynthesis of the eicosanoid Thromboxane A2, which unexpectedly activated parenchymal cell proliferation. Markers of Thromboxane A2 production were suppressed in adult macrophages after efferocytosis. Moreover, macrophage-neighboring neonatal cardiomyocytes expressed the Thromboxane A2 receptor, whose activation induced a metabolic shift supporting cellular proliferation. Our data reveal a fundamental age-defined macrophage response in which lipid mitogens produced during efferocytosis support receptor-mediated tissue regeneration.
2024-12-11 | GSE241928 | 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:During the critical process of homeostatic efferocytosis, macrophages clear apoptotic cells and subsequently transition to reparative functions that promote the resolution of inflammation and support tissue repair. Their inherent plasticity enables rapid changes in macrophage activity suited to specific microenvironments. However, the heterogeneity in their cell states also presents challenges in characterizing subsets of macrophages and analyzing their specific contributions post-efferocytosis. In this study, single-cell RNA sequencing data from bone-marrow derived macrophages engulfing apoptotic osteoblasts (OB) was used to characterize macrophage subpopulations enriched during efferocytosis. Clustering analysis revealed two subpopulations (c3 and c9) that were unique to efferocytic macrophages. These distinct subpopulations displayed a transcriptional profile characterized by enhanced glycolytic energy metabolism, along with an anti-inflammatory gene signature. Notably, HIF-1 signaling, glycolysis/gluconeogenesis, and carbon metabolism were among the top five most significantly enriched pathways in c3 and c9 macrophages. qRT-PCR analysis revealed that macrophages engulfing apoptotic OBs exhibited increased expression of key glycolytic enzymes and solute carriers, including Slc2a1, Pdk1, Ldha, and Slc16a3. Metabolomics analysis revealed a significant increase in intracellular lactate, phosphoenolpyruvic acid, glycerol-3-phosphate, 2-/3-glycerophosphate, and fructose-6-phosphate, indicative of enhanced glycolysis. In addition, efferocytic macrophages showed increased extracellular lactate production compared to control macrophages, as confirmed by lactate ELISA. The effects of lactate (0-20mM) on osteoblast mineralization, osteoclast differentiation and function, and macrophage-derived inflammatory factors were evaluated through various in vitro experiments. While no effect was seen in osteoblast mineralization, high lactate concentrations significantly reduced the number of multinucleated osteoclasts and their resorptive activity. Interestingly, extracellular lactate also significantly upregulated M2-like macrophage markers (Arg1, Il1rn, Klf4). These results support the concept that macrophage efferocytosis of apoptotic osteoblasts alters macrophage energy metabolism, which in turn plays a distinct and pivotal role in modulating the bone microenvironment.
2025-11-18 | GSE300915 | GEO
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
Project description:Efferocytosis triggers cellular reprogramming, including the induction of mRNA transcripts which encode anti-inflammatory cytokines that promote inflammation resolution. Our current understanding of this transcriptional response is largely informed from analysis of bulk phagocyte populations; however, this precludes the resolution of heterogeneity between individual macrophages and macrophage subsets. Moreover, phagocytes may contain so called “passenger” transcripts that originate from engulfed apoptotic bodies, thus obscuring the true transcriptional reprogramming of the phagocyte. To define the transcriptional diversity during efferocytosis, we utilized single-cell mRNA sequencing after co-cultivating macrophages with apoptotic cells. Importantly, transcriptomic analyses were performed after validating the disappearance of apoptotic cell-derived RNA sequences. Our findings reveal new heterogeneity of the efferocytic response at a single-cell resolution, particularly evident between F4/80+ MHCIILO and F4/80- MHCIIHI macrophage sub-populations. After exposure to apoptotic cells, the F4/80+ MHCIILO subset significantly induced pathways associated with tissue and cellular homeostasis, while the F4/80- MHCIIHI subset downregulated these putative signaling axes. Ablation of a canonical efferocytosis receptor, MerTK, blunted efferocytic signatures and led to the escalation of cell death-associated transcriptional signatures in F4/80+ MHCIILO macrophages. Taken together, our results newly elucidate the heterogenous transcriptional response of single-cell peritoneal macrophages after exposure to apoptotic cells.
2020-08-22 | GSE156234 | GEO