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Mechanosensitive Membrane Domains Regulate Calcium Entry in Arterial Endothelial Cells to Protect Against Inflammation

ABSTRACT: Mechanosensitive Membrane Domains Regulate Calcium Entry in Arterial Endothelial Cells to Protect Against Inflammation

PROVIDER: PRJNA1076497 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27966731_1.fastq.gz	Fastqsanger.gz
	SRR27966731_2.fastq.gz	Fastqsanger.gz
	SRR27966732_1.fastq.gz	Fastqsanger.gz
	SRR27966732_2.fastq.gz	Fastqsanger.gz
	SRR27966733_1.fastq.gz	Fastqsanger.gz

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Mechanosensitive Membrane Domains Regulate Calcium Entry in Arterial Endothelial Cells to Protect Against Inflammation

Project description:Endothelial cells (ECs) in the descending aorta are exposed to high laminar shear stress, which supports an anti-inflammatory phenotype. High laminar shear stress also supports flow-aligned cell elongation and front-rear polarity, but whether these are required for the anti-inflammatory phenotype is unclear. Here, we show that Caveolin-1-rich microdomains polarize to the downstream end of ECs exposed to continuous high laminar flow. These microdomains are characterized by high membrane rigidity, filamentous actin (F-actin), and raft-associated lipids. Transient receptor potential vanilloid-type 4 (Trpv4) ion channels are ubiquitously expressed on the plasma membrane but mediate localized Ca2+ entry only at these microdomains where they physically interact with clustered Caveolin-1. The resultant focal Ca2+ bursts activate endothelial nitric oxide synthase (eNOS) within the confines of these domains. Importantly, we find that signaling at these domains requires both cell body elongation and sustained flow. Finally, Trpv4 signaling at these domains is necessary and sufficient to suppress inflammatory gene expression, and ectopic activation of Trpv4 channels ameliorates the inflammatory response to stimuli both in vitro and in vivo. Our work reveals a novel polarized mechanosensitive signaling hub that dampens inflammatory gene expression in arterial ECs.

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Project description:Calcium signals are initiated in immune cells by the process of store-operated calcium entry (SOCE), where receptor activation triggers transient calcium release from the endoplasmic reticulum, followed by opening of plasma membrane calcium-release activated calcium (CRAC) channels. ORAI1, ORAI2 and ORAI3 are known to comprise the CRAC channel, however the contributions of individual isoforms to neutrophil function is not well understood. Here we show that loss of ORAI1 partially decreases calcium influx while loss of both ORAI1 and ORAI2 completely abolishes store-operated calcium entry. In other immune cell types, loss of ORAI2 enhances SOCE. In contrast, we find that ORAI2-deficient neutrophils display decreased calcium influx, which is correlated with measurable differences in regulation of neutrophil membrane potential via KCa3.1. Decreased SOCE in ORAI1-, ORAI2- and ORAI1/2-deficient neutrophils impairs multiple neutrophil functions including phagocytosis, degranulation, leukotriene and ROS production, rendering ORAI1/2-deficient mice highly susceptible to staphylococcal infection. This study demonstrates that ORAI1 and ORAI2 are the primary components of the neutrophil CRAC channel and identifies novel subpopulations of neutrophils where cell membrane potential functions as a rheostat to modulate the SOCE response. These findings have implications for new mechanisms that modulate neutrophil function during infection, acute and chronic inflammatory conditions, and cancer.

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