The mechanosensory channel Piezo1 Triggers Angiopoietin-Tie Signaling in the Lymphatics
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ABSTRACT:
PROVIDER: PRJNA872364 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21218564.fastq.gz | Fastqsanger.gz | |||
| SRR21218565.fastq.gz | Fastqsanger.gz | |||
| SRR21218566.fastq.gz | Fastqsanger.gz | |||
| SRR21218567.fastq.gz | Fastqsanger.gz |
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Project description:Angiopoietin-Tie1 signaling is required for lymphatic vascular integrity and both ANGPT2 and TIE1 genetic variants have been associated with lymphedema in patients1, 2. Concurrent with growth-factor signaling, mechanical forces sensed by lymphatic endothelial cells (LECs) are also needed to regulate lymphatics3, 4. How these two pathways might interact in the lymphatic system is unknown. Here, we identified a regulatory network in LECs linking activation of the mechanosensory channel, PIEZO1 to Angiopoietin-Tie signaling and repression of a downstream FOXO1 transcriptional response. RNAseq analysis of dermal LECs from Tie1-deficient embryos showed persistent FOXO1 activity with downregulation of LEC-associated genes including Ccl21a, Foxc2, Gata2 and Gja4, as well as increased expression of the mechanosensory channel, Piezo1. Activation of PIEZO1 in human dermal LECs (HDLECs) by the small molecule agonist, Yoda1, triggered exocytosis of the Tie ligand, Angiopoietin-2 (ANGPT2), activation of Tie/AKT/PI3K signaling and export of FOXO1 out of the nucleus. Our data identify a novel molecular pathway linking mechano-transduction to ANGPT2-Tie1 activity and dynamic modulation of FOXO1 activity needed for patterning and function of the lymphatic system
2024-03-05 | GSE211849 | GEO
Project description:Candida albicans metamorphoses from benign yeast to a rigid hyphae , becoming an opportunistic pathogen in immunocompromised patients. The process by which immune cells discern fungal transformations remains elusive. Here we report that the mechanosensitive ion channel Piezo1 is indispensable for recognizing fungal hyphae and triggering anti-fungal innate immune responses. Hyphae-triggered Piezo1 activation increased CLRs expression in innate immune cells by inducing the expression of C/EBPb via the Piezo1/CaMKs/CREB axis. In addition, Piezo1/CaMKs signaling activated kinases NDR1/2, which augmented NLRP3 inflammasome assembly and promoted hyphae-induced inflammation. Abolishing the yeast-to-hyphae transition dampens CLR and NLRP3 activation. Piezo1-deficient mice exhibit compromised clearance of C. albicans infection, whereas Piezo1 agonist amplifies C. albicans clearance. In addition, CaMKs, CREB or NDR1/2 inhibition exacerbates hyphae infections, like Piezo1 deficiency. Therefore, we ascertain Piezo1-mediated mechanotransduction as vital for immune surveillance and control of hyphal C. albicans, heralding Piezo1 agonist as a potential remedy for fungal infections.
2025-05-22 | GSE279850 | GEO
Project description:Candida albicans metamorphoses from benign yeast to a rigid hyphae , becoming an opportunistic pathogen in immunocompromised patients. The process by which immune cells discern fungal transformations remains elusive. Here we report that the mechanosensitive ion channel Piezo1 is indispensable for recognizing fungal hyphae and triggering anti-fungal innate immune responses. Hyphae-triggered Piezo1 activation increased CLRs expression in innate immune cells by inducing the expression of C/EBPb via the Piezo1/CaMKs/CREB axis. In addition, Piezo1/CaMKs signaling activated kinases NDR1/2, which augmented NLRP3 inflammasome assembly and promoted hyphae-induced inflammation. Abolishing the yeast-to-hyphae transition dampens CLR and NLRP3 activation. Piezo1-deficient mice exhibit compromised clearance of C. albicans infection, whereas Piezo1 agonist amplifies C. albicans clearance. In addition, CaMKs, CREB or NDR1/2 inhibition exacerbates hyphae infections, like Piezo1 deficiency. Therefore, we ascertain Piezo1-mediated mechanotransduction as vital for immune surveillance and control of hyphal C. albicans, heralding Piezo1 agonist as a potential remedy for fungal infections.
2025-05-21 | GSE293094 | GEO
Project description:Immunotherapy using immune checkpoint inhibitors (ICI) has revolutionized the management of melanoma. Although the anti-PD-1 antibodies induce a 40% objective response rate (ORR) in advanced melanoma patients, the majority of patients have a primary resistance or develop a secondary resistance (Robert et al. 2015). Many resistance mechanisms have been described including the loss of the expression of class I MHC, the alteration of antigen presentation, JAK/STAT pathway mutation, or the overexpression of another inhibitory molecule (LAG-3, TIM-3, …). It was also known that immunosuppressive cells such as myeloid-derived Suppressor Cells (MDSC) can negatively impact the efficacy of anti-PD-1 therapy (Limagne et al. 2019). MDSCs are a group of immunosuppressive heterogenous cells found in many cancers that inhibit antitumor T cell functions by several mechanisms. We previously described in lung cancer a novel subpopulation of monocytic MDSC (M-MDSC) overexpressing TIE-2 that mediate inhibition of antitumor T cell responses after angiopoietin-2 (ANGPT2) exposure. Furthermore, we found, that a high level of circulating TIE-2+ M-MDSC and ANGPT2 in melanoma patients is associated with a poor prognosis by inhibiting anti-melanoma T-cell responses (Marguier et al. 2022).TIE-2 is a tyrosine kinase with immunoglobulin and EGF homology domains. This receptor was mainly expressed by endothelial cells but can be expressed by tumor cells and some immune cells such as monocytes. TIE-2 binds to the pro-angiogenic factor ANGPT2 which is involved in tumor neo-angiogenesis. Recent findings in melanoma also showed the implication of ANGPT2 in resistance to anti-PD-1 therapy by promoting the exclusion of T cells (Park et al. 2023). Thus, we assumed that TIE-2+ M-MDSC would be involved in this negative impact of ANGPT2 on anti-PD-1 therapy.
2025-04-08 | GSE288083 | GEO
Project description:Although cells of the immune system experience force and pressure throughout their lifecycle, almost nothing is known about how these mechanical processes regulate the immune response. Immune cells in highly mechanical organs, such as the lung, are constantly exposed to tonic and dynamically changing mechanical cues. Here using reverse genetics, we show that myeloid cells respond to force and alterations in cyclical hydrostatic pressure (CHP) via the mechanosensory ion channel (MSIC) PIEZO1. Unbiased RNA-sequencing from macrophages subjected to CHP reveals a striking state of proinflammatory reprogramming. We report a novel mechanosensory-immune signaling circuit which PIEZO1 initiates in response to CHP, activating c-JUN, upregulating Endothelin-1 (EDN1), and stabilizing HIF1α to facilitate a prolonged program of proinflammatory mediators. Using mice conditionally deficient of PIEZO1 in myeloid cells, and cellular depletion assays, we show infiltrating monocytes respond to cyclical force to recruit neutrophils and clear pulmonary Pseudomonas aeruginosa infection. Furthermore, myeloid PIEZO1 also drove lung pathology in a mouse model of pulmonary fibrosis. Our results demonstrate a novel environmental sensory axis that myeloid cells recognize to mount an inflammatory response, and is the first report showing a physiological role for PIEZO1 and mechanosensation in immunity.
2019-08-21 | GSE133069 | GEO
Project description:PIEZO1 is a mechanically-activated ion channel that contributes to flow sensing in vascular endothelium. Moreover, deletion of endothelial PIEZO1 was recently found to suppress activation of Notch1 target genes in hepatic microvascular endothelium. Here, because of the liver’s dominant role in lipid regulation, we set out to test the novel hypothesis that endothelial PIEZO1 regulates hepatic lipid homeostasis. We performed bulk RNA sequencing on PIEZO1-deleted mice exposed to chow and high fat diets. Our transcriptomics analysis reveal unexpected relevance to lipid and glucose homeostasis.
2024-06-29 | E-MTAB-9996 | biostudies-arrayexpress
Project description:Piezo1 initiates host immune defense against pathogenic fungi through mechanosensory recognition of Candida albicans hyphae
| PRJNA1174786 | ENA
Project description:Piezo1 initiates host immune defense against pathogenic fungi through mechanosensory recognition of Candida albicans hyphae
| PRJNA1242795 | ENA
Project description:Mechanical overload of the vascular wall is a pathological hallmark of life-threatening abdominal aortic aneurysms (AAA). However, how this mechanical stress resonates at the unicellular level of vascular smooth muscle cells (VSMC) is undefined. Here, we combined novel tweezers-based micromechanical system and single-cell RNA sequencing to map defective mechano-phenotype signatures of VSMC in AAA. Notably, theoretical modelling predicted that cytoskeleton alterations fueled cell membrane tension of VSMC, thereby modulating their mechanoallostatic responses which were validated by live micromechanical measurements. Mechanistically, VSMC gradually adopted a mechanically solid-like state by upregulating CSK crosslinker, α-actinin2, in the presence of AAA-promoting signal, Netrin-1, thereby directly powering the activity of mechanosensory ion channel Piezo1. Inhibition of Piezo1 prevented mice from developing AAA by alleviating pathological vascular remodeling. Our findings demonstrate that deviations of mechanosensation behaviors of VSMC is detrimental for AAA and identifies Piezo1 as a novel culprit of mechanically fatigued aorta in AAA.
2021-11-01 | GSE186865 | GEO
Project description:The propeller-shaped blades of the PIEZO1 and PIEZO2 ion channels partition into the plasma membrane and respond to indentation or stretching of the lipid bilayer, thus converting mechanical forces into signals that can be interpreted by cells, in the form of calcium flux and changes in membrane potential. While PIEZO channels participate in diverse physiological processes, from sensing the shear stress of blood flow in the vasculature to detecting a light touch on the surface of the skin, the molecular details that enable these mechanosensors to tune their responses over a vast dynamic range of forces remain largely uncharacterized. To survey the molecular landscape surrounding PIEZO channels at the cell surface, we employed a mass spectrometry-based proteomic approach to capture and identify extracellularly exposed proteins in the vicinity of PIEZO1. This PIEZO1-proximal interactome was enriched in surface proteins localized to cell junctions and signaling hubs within the plasma membrane. Functional screening of these interaction candidates by calcium imaging and electrophysiology in an overexpression system identified the adhesion molecule CADM1/SynCAM that slows the inactivation kinetics of PIEZO1 with little effect on PIEZO2. Conversely, we found that CADM1 knockdown accelerates inactivation of endogenous PIEZO1 in Neuro-2a cells. Systematic deletion of CADM1 domains indicate that the transmembrane region is critical for the observed effects on PIEZO1, suggesting that modulation of inactivation is mediated by interactions in or near the lipid bilayer.
2024-10-30 | PXD054618 | Pride