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Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling

ABSTRACT: Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling

PROVIDER: PRJNA602422 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10918622_1.fastq.gz	Fastqsanger.gz
	SRR10918622_2.fastq.gz	Fastqsanger.gz
	SRR10918623_1.fastq.gz	Fastqsanger.gz
	SRR10918623_2.fastq.gz	Fastqsanger.gz
	SRR10918624_1.fastq.gz	Fastqsanger.gz

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Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling

Project description:We found different expression between glycolytic enzymes and TCA pathway in bone marrow neutrophils following LPS treatment, using RNAseq. This enable us to uncover the important role of glycolysis in activated neutrophils and the effect of HIF-1alpha on this pathway

2020-06-03 | GSE143978 | GEO

Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling.

Project description:Neutrophils provide first line of host defense against bacterial infections utilizing glycolysis for their effector functions. How glycolysis and its major byproduct lactate are triggered in bone marrow (BM) neutrophils and their contribution to neutrophil mobilization in acute inflammation is not clear. Here we report that bacterial lipopolysaccharides (LPS) or Salmonella Typhimurium triggers lactate release by increasing glycolysis, NADPH-oxidase-mediated reactive oxygen species and HIF-1α levels in BM neutrophils. Increased release of BM lactate preferentially promotes neutrophil mobilization by reducing endothelial VE-Cadherin expression, increasing BM vascular permeability via endothelial lactate-receptor GPR81 signaling. GPR81-/- mice mobilize reduced levels of neutrophils in response to LPS, unless rescued by VE-Cadherin disrupting antibodies. Lactate administration also induces release of the BM neutrophil mobilizers G-CSF, CXCL1 and CXCL2, indicating that this metabolite drives neutrophil mobilization via multiple pathways. Our study reveals a metabolic crosstalk between lactate-producing neutrophils and BM endothelium, which controls neutrophil mobilization under bacterial infection.

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Elevated Lactate in AML Bone Marrow Contributes to Macrophage Polarization via GPR81 Signaling

Project description:Interactions between acute myeloid leukemia (AML) and the bone marrow microenvironment (BMME) are critical to leukemia progression and chemoresistance. In the solid tumor microenvironment, altered metabolite levels contribute to cancer progression. We performed a metabolomic analysis of AML patient bone marrow serum, revealing increased metabolites compared to age- and sex-matched controls. The most highly elevated metabolite in the AML BMME was lactate. Lactate signaling in solid tumors induces immunosuppressive tumor-associated macrophages and correlates with poor prognosis. This has not yet been studied in the leukemic BMME. Herein, we describe the role of lactate in the polarization of leukemia-associated macrophages (LAMs). Using a murine AML model of blast crisis chronic myelogenous leukemia (bcCML), we characterize the suppressive phenotype of LAMs by surface markers, transcriptomics, and cytokine profiling. Then, mice genetically lacking GPR81, the extracellular lactate receptor, were used to demonstrate GPR81 signaling as a mechanism of both the polarization of LAMs and the direct support of leukemia cells. Furthermore, elevated lactate diminished the function of hematopoietic progenitors and reduced stromal support for normal hematopoiesis. We report microenvironmental lactate as a mechanism of AML-induced immunosuppression and leukemic progression, thus identifying GPR81 signaling as an exciting and novel therapeutic target for treating this devastating disease.

2026-03-11 | GSE313457 | GEO

Lactate receptor GPR81 drives breast cancer growth and invasiveness through regulation of ECM properties and Notch ligand DLL4

Project description:The lactate receptor GPR81 contributes to cancer development, yet the mechanisms remain unclear. Here, we show that GPR81 is upregulated in human cancers and further upregulated by extracellular lactate and three-dimensional growth of breast cancer spheroids. GPR81 knockdown (KD) increased spheroid necrosis and reduced invasion and in vivo tumor growth. GPR81 KD altered GO terms relating to extracellular matrix (ECM) and cell adhesion, including upregulation of Protocadherin-7 (PCDH7), which exhibited a striking, clustered expression in spheroids. Single cell analysis revealed that PCDH7 was inversely related with Ki-67 and co-clustered with other GPR81 KD-upregulated genes including Ephrin-type-A receptor-7 (EPHA7). The matricellular protein SPARC and the Notch ligand Delta-like-4 (DLL4), were downregulated upon GPR81 KD, and their KD elicited spheroid necrosis (DLL4) and inhibited invasion. We conclude that GPR81 supports breast cancer aggressiveness at least in part via SPARC and DLL4. Our findings substantiate GPR81 as a promising target in breast cancer treatment.

2022-05-23 | GSE203441 | GEO

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Project description:Here we uncover that neutrophils release a previously unidentified fibrillar complex, named proteoglycofili (PGF) under hypoxic conditions or upon bacterial infection, using Shigella as a model. PGF are preferentially released by neutrophils over NETs upon bacterial infection. We demonstrated that PGF are released by living neutrophils, do not contain DNA and are mainly composed of granule proteins. We revealed that the fibrillar structure of PGF is sustained by two glycosaminoglycans (GAGs), hyaluronic acid and chondroitin sulfate, firstly identified here to be released by neutrophils. We demonstrated that PGF are potent antimicrobials, which degrade virulence factors of Shigella and block its growth, similarly with E. coli or Salmonella. We confirmed that GAGs were essential for PGF antimicrobial activity in vitro and in vivo. Beyond bacterial infections, our results strongly suggest that GAGs may be released by neutrophils in a broad range of inflammatory diseases to be further explored.

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Elevated Lactate in AML Bone Marrow Contributes to Macrophage Polarization via GPR81 Signaling

Project description:Elevated Lactate in AML Bone Marrow Contributes to Macrophage Polarization via GPR81 Signaling

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Oxidized mitochondrial nucleoids released by neutrophils drive type I Interferon production in human lupus

Project description:Autoantibodies against nucleic acids and excessive type I Interferon (IFN) are hallmarks of human Systemic Lupus Erythematosus (SLE). We previously reported that SLE neutrophils, exposed to TLR7-agonist autoantibodies, release interferogenic DNA, which we now demonstrate to be of mitochondrial origin. We further show that healthy human neutrophils do not complete mitophagy upon induction of mitochondrial damage. Rather, they extrude mitochondrial components, including DNA (mtDNA), devoid of oxidized residues. When MtDNA undergoes oxidation, it is directly routed to lysosomes for degradation. This rerouting requires dissociation from the transcription factor TFAM, a dual high mobility group (HMG) protein involved in maintenance and compaction of the mitochondrial genome into nucleoids. Exposure of SLE neutrophils, or healthy IFNprimed neutrophils, to anti-RNP autoantibodies blocks TFAM phosphorylation, a necessary step for nucleoid dissociation. Consequently, oxidized nucleoids accumulate within mitochondria and are eventually extruded as potent interferogenic complexes. In support of the in vivo relevance of this phenomenon, mitochondrial retention of oxidized nucleoids is a feature of SLE blood neutrophils, and autoantibodies against oxidized mtDNA are present in a fraction of patients. This pathway represents a novel therapeutic target in human SLE. 4 samples, no replicates, 2 controls. 2 samples are Neutrophils cultured with and without CCCP (control). 2 samples are Monocytes cultured with and without CCCP (control).

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Expression data from bone marrow (BM) neutrophils

Project description:We employed GeneChip analysis to investigate the global gene expression profiles of neutrophils from BM Gr-1high/CD48– neutrophils were sorted from the BM of C57BL/6 mice by FACS in two independent experiments

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Neutrophils facilitate the epicardial regenerative response after zebrafish heart injury

Project description:Despite extensive studies on endogenous heart regeneration within the past 20 years, the players involved in initiating early regeneration events are far from clear. Here, we assessed the function of neutrophils, the first-responder cells to tissue damage, during heart regeneration. We detected rapid neutrophil mobilization to the injury site after ventricular amputation, peaking at 1-day post-amputation (dpa) and resolving by 3 dpa. Further analyses indicated neutrophil mobilization coincides with peak epicardial cell proliferation and recruited neutrophils associated with activated, expanding epicardial cells at 1 dpa. Neutrophil depletion inhibited myocardial regeneration and significantly reduced epicardial cell expansion, proliferation, and activation. To explore the molecular mechanism of neutrophils on the epicardial regenerative response, we performed scRNA-seq analysis of 1 dpa neutrophils and identified enrichment of the FGF and ERK signaling pathways. Pharmacological inhibition of FGF signaling indicated its’ requirement for epicardial cell expansion, while neutrophil depletion blocked ERK signaling activation in epicardial cells. Altogether, our studies revealed that neutrophils quickly induce epicardial cells, which later accumulate at the injury site and contribute to heart regeneration.

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Proteoglycofili are glycosaminoglycan-containing fibrillar components released by neutrophils to neutralize bacteria

Project description:Proteoglycofili are glycosaminoglycan-containing fibrillar components released by neutrophils to neutralize bacteria

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