Macrophage Dicer promotes tolerogenic apoptotic cell clearance and immune tolerance by inhibiting pentose phosphate pathway activity.
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ABSTRACT:
SUBMITTER: Mao Q
PROVIDER: S-EPMC8245631 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The efficient removal of apoptotic cells (ACs), a process termed as efferocytosis, is essential for immune homeostasis. While recent work has established an important interplay between efferocytosis and cellular metabolic changing, underlying mechanisms remain poorly known. Here, we discovered that pentose phosphate pathway (PPP) regulates tolerogenic ACs clearance and immune tolerance. ACs decreased levels of PPP-related genes and metabolites in macrophages. AG1, the agonist of PPP, increased the activity of PPP but greatly reduced macrophage phagocytosis of ACs and enhanced the inflammatory response during efferocytosis. miR-323-5p regulated the expression of PPP-related genes and its levels increased during efferocytosis. miR-323-5p inhibitor greatly promoted levels of PPP-related genes, reduced the macrophage phagocytosis of ACs, and increased inflammatory response during efferocytosis, suggesting that miR-323-5p was essential in regulating PPP activity and ACs clearance in macrophages. Correspondingly, the PPP agonist AG1 exacerbated the lupus-like symptoms in the AC-induced systemic lupus erythematosus (SLE) model. Our study reveals that regulating PPP-dependent metabolic reprogramming is critical for tolerogenic ACs phagocytosis and immune tolerance.
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Project description:As the body continues to grow and age, it becomes essential to maintain a balance between living and dying cells. Macrophages and dendritic cells play a central role in discriminating among viable, apoptotic, and necrotic cells, as selective and efficient phagocytes, without inducing inappropriate inflammation or immune responses. A great deal has been learnt concerning clearance receptors for modified and non-self-ligands on potential targets, mediating their eventual uptake, disposal, and replacement. In this essay, we assess current understanding of the phagocytic recognition of apoptotic cells within their tissue environment; we conclude that efferocytosis constitutes a more complex process than simply removal of corpses, with regulatory interactions between the target and effector cells, which determine the outcome of this homeostatic process.
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Project description:Hepatocellular carcinoma (HCC) has a poor prognosis due to the rapid disease progression and early metastasis. The metabolism program determines the proliferation and metastasis of HCC; however, the metabolic approach to treat HCC remains uncovered. Here, by analyzing the liver cell single-cell sequencing data from HCC patients and healthy individuals, we found that 6-phosphogluconolactonase (PGLS), a cytosolic enzyme in the oxidative phase of the pentose phosphate pathway (PPP), expressing cells are associated with undifferentiated HCC subtypes. The Cancer Genome Atlas database showed that high PGLS expression was correlated with the poor prognosis in HCC patients. Knockdown or pharmaceutical inhibition of PGLS impaired the proliferation, migration, and invasion capacities of HCC cell lines, Hep3b and Huh7. Mechanistically, PGLS inhibition repressed the PPP, resulting in increased reactive oxygen species level that decreased proliferation and metastasis and increased apoptosis in HCC cells. Overall, our study showed that PGLS is a potential therapeutic target for HCC treatment through impacting the metabolic program in HCC cells.
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Project description:G-quadruplexes form in guanine-rich regions of DNA and the presence of these structures at telomeres prevents the activity of telomerase in vitro. Ligands such as the cationic porphyrin TMPyP4 stabilise G-quadruplexes and are therefore under investigation for their potential use as anti-cancer drugs. In order to investigate the mechanism of action of TMPyP4 in vivo, we carried out a genome-wide screen in the budding yeast Saccharomyces cerevisiae. We found that deletion of key pentose phosphate pathway (PPP) genes increased the sensitivity of yeast to the presence of TMPyP4. The PPP plays an important role in the oxidative stress response and sensitivity to TMPyP4 also increased when genes involved in the oxidative stress response, CCS1 and YAP1, were deleted. For comparison we also report genome wide-screens using hydrogen peroxide, which causes oxidative stress, RHPS4, another G-quadruplex binder and hydroxyurea, an S phase poison. We found that a number of TMPyP4-sensitive strains are also sensitive to hydrogen peroxide in a genome-wide screen. Overall our results suggest that treatment with TMPyP4 results in light-dependent oxidative stress response in budding yeast, and that this, rather than G-quadruplex binding, is the major route to cytotoxicity. Our results have implications for the usefulness and mechanism of action of TMPyP4.
| S-EPMC3680382 | biostudies-literature
Project description:Metabolic reprogramming has emerged as a crucial regulator of immune cell activation but how systemic metabolism influences immune cell metabolism and function remains to be investigated. To investigate the effect of dyslipidemia on immune cell metabolism, we performed in-depth transcriptional, metabolic and functional characterization of macrophages isolated from hypercholesterolemic mice. Systemic metabolic changes in such mice alter cellular macrophage metabolism and attenuate inflammatory macrophage responses. In addition to diminished maximal mitochondrial respiration, hypercholesterolemia reduces the LPS-mediated induction of the pentose phosphate pathway (PPP) and the Nrf2-mediated oxidative stress response. Our observation that suppression of the PPP diminishes LPS-induced cytokine secretion supports the notion that this pathway contributes to inflammatory macrophage responses. Overall, this study reveals that systemic and cellular metabolism are strongly interconnected, together dictating macrophage phenotype and function.
2018-10-31 | GSE107412 | GEO
Project description:We previously showed that antigen immunization in the presence of the immunosuppressant dexamethasone (a strategy we termed "suppressed immunization") could tolerize established recall responses of T cells. However, the mechanism by which dexamethasone acts as a tolerogenic adjuvant has remained unclear. In the present study, we show that dexamethasone enriches CD11c(lo) CD40(lo) macrophages in a dose-dependent manner in the spleen and peripheral lymph nodes of mice by depleting all other CD11c(+) CD40(+) cells including dendritic cells. The enriched macrophages display a distinct MHC class II (MHC II)(lo) CD86(hi) phenotype. Upon activation by antigen in vivo, CD11c(lo) CD40(lo) macrophages upregulate IL-10, a classic marker for tolerogenic antigen-presenting cells, and elicit a serum IL-10 response. When presenting antigen in vivo, these cells do not elicit recall responses from memory T cells, but rather stimulate the expansion of antigen-specific regulatory T cells. Moreover, the depletion of CD11c(lo) CD40(lo) macrophages during suppressed immunization diminishes the tolerogenic efficacy of the treatment. These results indicate that dexamethasone acts as a tolerogenic adjuvant partly by enriching the CD11c(lo) CD40(lo) tolerogenic macrophages.
| S-EPMC3697049 | biostudies-literature
Project description:Heme is an essential cofactor for numerous cellular functions, but release of free heme during hemolysis results in oxidative tissue damage, vascular dysfunction, and inflammation. Macrophages play a key protective role in heme clearance; however, the mechanisms that regulate metabolic adaptations that are required for effective heme degradation remain unclear. Here we demonstrate that heme loading drives a unique bioenergetic switch in macrophages, which involves a metabolic shift from oxidative phosphorylation toward glucose consumption. Metabolomic and transcriptional analysis of heme-loaded macrophages revealed that glucose is funneled into the pentose phosphate pathway (PPP), which is indispensable for efficient heme detoxification and is required to maintain redox homeostasis. We demonstrate that the metabolic shift to the PPP is controlled by heme oxygenase-dependent generation of carbon monoxide (CO). Finally, we show that PPP upregulation occurs in vivo in organ systems central to heme clearance and that PPP activity correlates with heme levels in mouse sickle cell disease (SCD). Together, our findings demonstrate that metabolic adaptation to heme detoxification in macrophages requires a shift to the PPP that is induced by heme-derived CO, suggesting pharmacologic targeting of macrophage metabolism as a novel therapeutic strategy to improve heme clearance in patients with hemolytic disorders.
| S-EPMC7515686 | biostudies-literature
Project description:Macrophages rapidly engulf apoptotic cells to limit the release of noxious cellular contents and to restrict autoimmune responses against self antigens. Although factors participating in recognition and engulfment of apoptotic cells have been identified, the transcriptional basis for the sensing and the silent disposal of apoptotic cells is unknown. Here we show that peroxisome proliferator-activated receptor-delta (PPAR-delta) is induced when macrophages engulf apoptotic cells and functions as a transcriptional sensor of dying cells. Genetic deletion of PPAR-delta decreases expression of opsonins such as complement component-1qb (C1qb), resulting in impairment of apoptotic cell clearance and reduction in anti-inflammatory cytokine production. This increases autoantibody production and predisposes global and macrophage-specific Ppard(-/-) mice to autoimmune kidney disease, a phenotype resembling the human disease systemic lupus erythematosus. Thus, PPAR-delta has a pivotal role in orchestrating the timely disposal of apoptotic cells by macrophages, ensuring that tolerance to self is maintained.
| S-EPMC2783696 | biostudies-literature
Project description:AimsInflammation and possibly hypoxia largely affect glucose utilization in atherosclerotic arteries, which could alter many metabolic systems. However, metabolic changes in atherosclerotic plaques remain unknown. The present study aims to identify changes in metabolic systems relative to glucose uptake and hypoxia in rabbit atherosclerotic arteries and cultured macrophages.MethodsMacrophage-rich or smooth muscle cell (SMC)-rich neointima was created by balloon injury in the iliac-femoral arteries of rabbits fed with a 0.5% cholesterol diet or a conventional diet. THP-1 macrophages stimulated with lipopolysaccharides (LPS) and interferon-γ (INFγ) were cultured under normoxic and hypoxic conditions. We evaluated comprehensive arterial and macrophage metabolism by performing metabolomic analyses using capillary electrophoresis-time of flight mass spectrometry. We evaluated glucose uptake and its relationship to vascular hypoxia using (18)F-fluorodeoxyglucose ((18)F-FDG) and pimonidazole, a marker of hypoxia.ResultsThe levels of many metabolites increased in the iliac-femoral arteries with macrophage-rich neointima, compared with those that were not injured and those with SMC-rich neointima (glycolysis, 4 of 9; pentose phosphate pathway, 4 of 6; tricarboxylic acid cycle, 4 of 6; nucleotides, 10 of 20). The uptake of (18)F-FDG in arterial walls measured by autoradiography positively correlated with macrophage- and pimonidazole-immunopositive areas (r = 0.76, and r = 0.59 respectively; n = 69 for both; p<0.0001). Pimonidazole immunoreactivity was closely localized with the nuclear translocation of hypoxia inducible factor-1α and hexokinase II expression in macrophage-rich neointima. The levels of glycolytic (8 of 8) and pentose phosphate pathway (4 of 6) metabolites increased in LPS and INFγ stimulated macrophages under hypoxic but not normoxic condition. Plasminogen activator inhibitor-1 protein levels in the supernatant were closely associated with metabolic pathways in the macrophages.ConclusionInfiltrative macrophages in atherosclerotic arteries might affect metabolic systems, and hypoxia but not classical activation might augment glycolytic and pentose phosphate pathways in macrophages.
| S-EPMC3900532 | biostudies-literature
Project description:Resolution of inflammation is essential for tissue homeostasis and represents a promising approach to inflammatory disorders. Here we found that developmental endothelial locus-1 (DEL-1), a secreted protein that inhibits leukocyte-endothelial adhesion and inflammation initiation, also functions as a non-redundant downstream effector in inflammation clearance. In human and mouse periodontitis, waning of inflammation was correlated with DEL-1 upregulation, whereas resolution of experimental periodontitis failed in DEL-1 deficiency. This concept was mechanistically substantiated in acute monosodium-urate-crystal-induced inflammation, where the pro-resolution function of DEL-1 was attributed to effective apoptotic neutrophil clearance (efferocytosis). DEL-1-mediated efferocytosis induced liver X receptor-dependent macrophage reprogramming to a pro-resolving phenotype and was required for optimal production of at least certain specific pro-resolving mediators. Experiments in transgenic mice with cell-specific overexpression of DEL-1 linked its anti-leukocyte-recruitment action to endothelial cell-derived DEL-1 and its efferocytic/pro-resolving action to macrophage-derived DEL-1. Thus, the compartmentalized expression of DEL-1 facilitates distinct homeostatic functions in an appropriate context that can be harnessed therapeutically.
| S-EPMC6291356 | biostudies-literature