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Project description:Macrophage histone lactylation during ischemia induced-muscle regeneration
| PRJNA1068601 | ENA
Project description:After injury, muscles require fully functional macrophages to recover completely. During muscle regeneration, macrophages transition from a pro-inflammatory to a pro-restorative phenotype ensures the proper regeneration. Lactate is a crucial molecule for muscle-residing macrophage polarisation. Histone lactylation, a direct derivative of lactate, has been implicated in macrophage polarisation in vitro . In this work, we show for the first time that macrophages recruited to the muscle after ischemic injury modify their histone lactylome between 2 and 4 days post injury. Absolute histone lactylation levels increase significantly. Although subtly, also the genomic enrichment of H3K18la changes from 2 to 4 days post injury and this correlates with gene expression changes. Interestingly, we find that H3K18la genomic enrichment changes from day 2 to day 4 post injury are predictive for gene expression changes later in time, from day 4 to day 7, rather than being a reflection of past gene expression changes from day 1 to day 2. Our results suggest that histone lactylation dynamics are functionally important for the resolving action of macrophages during muscle regeneration.
2024-04-08 | GSE254129 | GEO
Project description:After injury, muscles require fully functional macrophages to recover completely. During muscle regeneration, macrophages transition from a pro-inflammatory to a pro-restorative phenotype ensures the proper regeneration. Lactate is a crucial molecule for muscle-residing macrophage polarisation. Histone lactylation, a direct derivative of lactate, has been implicated in macrophage polarisation in vitro . In this work, we show for the first time that macrophages recruited to the muscle after ischemic injury modify their histone lactylome between 2 and 4 days post injury. Absolute histone lactylation levels increase significantly. Although subtly, also the genomic enrichment of H3K18la changes from 2 to 4 days post injury and this correlates with gene expression changes. Interestingly, we find that H3K18la genomic enrichment changes from day 2 to day 4 post injury are predictive for gene expression changes later in time, from day 4 to day 7, rather than being a reflection of past gene expression changes from day 1 to day 2. Our results suggest that histone lactylation dynamics are functionally important for the resolving action of macrophages during muscle regeneration.
2024-04-08 | GSE254128 | GEO
Project description:ObjectivesWe have previously shown that lactate is an essential metabolite for macrophage polarisation during ischemia-induced muscle regeneration. Recent in vitro work has implicated histone lactylation, a direct derivative of lactate, in macrophage polarisation. Here, we explore the in vivo relevance of histone lactylation for macrophage polarisation after muscle injury.MethodsTo evaluate macrophage dynamics during muscle regeneration, we subjected mice to ischemia-induced muscle damage by ligating the femoral artery. Muscle samples were harvested at 1, 2, 4, and 7 days post injury (dpi). CD45+CD11b+F4/80+CD64+ macrophages were isolated and processed for RNA sequencing, Western Blotting, and CUT&Tag-sequencing to investigate gene expression, histone lactylation levels, and histone lactylation genomic localisation and enrichment, respectively.ResultsWe show that, over time, macrophages in the injured muscle undergo extensive gene expression changes, which are similar in nature and in timing to those seen after other types of muscle-injuries. We find that the macrophage histone lactylome is modified between 2 and 4 dpi, which is a crucial window for macrophage polarisation. Absolute histone lactylation levels increase, and, although subtly, the genomic enrichment of H3K18la changes. Overall, we find that histone lactylation is important at both promoter and enhancer elements. Lastly, H3K18la genomic profile changes from 2 to 4 dpi were predictive for gene expression changes later in time, rather than being a reflection of prior gene expression changes.ConclusionsOur results suggest that histone lactylation dynamics are functionally important for the function of macrophages during muscle regeneration.
| S-EPMC11002880 | biostudies-literature
Project description:Macrophage histone lactylation during ischemia induced-muscle regeneration [CUT&Tag]
| PRJNA1068610 | ENA
Project description:Macrophage histone lactylation during ischemia induced-muscle regeneration [RNA-Seq]
| PRJNA1068612 | ENA
Project description:Augmented glycolysis due to metabolic reprogramming in lung myofibroblasts is critical to their profibrotic phenotype. The primary glycolysis byproduct, lactate, is also secreted into the extracellular milieu, together with which myofibroblasts and macrophages form a spatially restricted site usually described as fibrotic niche. Therefore, we hypothesized that myofibroblast glycolysis might have a non-cell autonomous effect through lactate regulating the pathogenic phenotype of alveolar macrophages. Here, we demonstrated that there was a markedly increased lactate in the conditioned media of TGF-β1 (transforming growth factor-β1)-induced lung myofibroblasts and in the BAL fluids (BALFs) from mice with TGF-β1- or bleomycin-induced lung fibrosis. Importantly, the media and BALFs promoted profibrotic mediator expression in macrophages. Mechanistically, lactate induced histone lactylation in the promoters of the profibrotic genes in macrophages, consistent with the upregulation of this epigenetic modification in these cells in the fibrotic lungs. The lactate inductions of the histone lactylation and profibrotic gene expression were mediated by p300, as evidenced by their diminished concentrations in p300-knockdown macrophages. Collectively, our study establishes that in addition to protein, lipid, and nucleic acid molecules, a metabolite can also mediate intercellular regulations in the setting of lung fibrosis. Our findings shed new light on the mechanism underlying the key contribution of myofibroblast glycolysis to the pathogenesis of lung fibrosis.
| S-EPMC7780997 | biostudies-literature
Project description:The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia. Therefore, macrophage-based therapeutic targets need to be explored for ischemic disease. In the current study, we found that the mRNA levels of scavenger receptor A1 ( Sr-a1) were elevated in patients with critical limb ischemia, based on an analysis of the Gene Expression Omnibus data. We then investigated the role and underlying mechanisms of macrophage SR-A1 in a mouse hindlimb ischemia (HLI) model. Compared with the Sr-a1 fl/fl mice, the Lyz Cre/+/ Sr-a1 flox/flox ( Sr-a1 ΔMΦ) mice showed significantly reduced laser Doppler blood flow in the ischemic limb on day seven after HLI. Consistently, histological analysis revealed that the ischemic limb of the Sr-a1 ΔMΦ mice exhibited more severe and prolonged necrotic morphology, inflammation, fibrosis, decreased vessel density, and delayed regeneration than that of the control Sr-a1 fl/fl mice. Furthermore, restoring wild-type myeloid cells to the Sr-a1 knockout mice effectively improved the Doppler perfusion in the ischemic limb and mitigated skeletal muscle damage seven days after HLI. Consistent with these in vivo findings, co-cultivating macrophages with the mouse myoblast cell line C2C12 revealed that the Sr-a1 -/- bone marrow macrophages significantly inhibited myoblast differentiation in vitro. Mechanistically, SR-A1 enhanced the skeletal muscle regeneration in response to HLI by inhibiting oncostatin M production via suppression of the NF-κB signaling activation. These findings indicate that SR-A1 may be a promising candidate protein to improve tissue repair and regeneration in peripheral ischemic arterial disease.
| S-EPMC11873590 | biostudies-literature
Project description:Endothelial cell (EC)-derived signals contribute to organ regeneration, but angiocrine metabolic communication is not described. We found that EC-specific loss of the glycolytic regulator pfkfb3 reduced ischemic hindlimb revascularization and impaired muscle regeneration. This was caused by the reduced ability of macrophages to adopt a proangiogenic and proregenerative M2-like phenotype. Mechanistically, loss of pfkfb3 reduced lactate secretion by ECs and lowered lactate levels in the ischemic muscle. Addition of lactate to pfkfb3-deficient ECs restored M2-like polarization in an MCT1-dependent fashion. Lactate shuttling by ECs enabled macrophages to promote proliferation and fusion of muscle progenitors. Moreover, VEGF production by lactate-polarized macrophages was increased, resulting in a positive feedback loop that further stimulated angiogenesis. Finally, increasing lactate levels during ischemia rescued macrophage polarization and improved muscle reperfusion and regeneration, whereas macrophage-specific mct1 deletion prevented M2-like polarization. In summary, ECs exploit glycolysis for angiocrine lactate shuttling to steer muscle regeneration from ischemia.
| S-EPMC7267778 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-05-01 | GSE226008 | GEO