sphingosine-1-phosphate and cyclic-guanosine-monophosphate-adenosine-monophosphate

Acute lung injury (ALI) is a lethal inflammatory lung disorder whose incidence is on the rise. Alveolar macrophages normally act to resolve inflammation, but when dysregulated they can provoke ALI. We demonstrate that monocyte-derived macrophages (CD11b

Topics: Adoptive Transfer; Animals; CD11b Antigen; Cytokines; Humans; Inflammation; Inflammation Mediators; Lung; Lysophospholipids; Macrophages, Alveolar; Membrane Proteins; Mice, Inbred C57BL; Nucleotides, Cyclic; Phosphotransferases (Alcohol Group Acceptor); Pseudomonas aeruginosa; Signal Transduction; Sphingosine; U937 Cells

Extracellular 2'3'-cyclic-GMP-AMP (cGAMP) is an immunotransmitter exported by diseased cells and imported into host cells to activate the innate immune STING pathway. We previously identified SLC19A1 as a cGAMP importer, but its use across human cell lines is limited. Here, we identify LRRC8A heteromeric channels, better known as volume-regulated anion channels (VRAC), as widely expressed cGAMP transporters. LRRC8A forms complexes with LRRC8C and/or LRRC8E, depending on their expression levels, to transport cGAMP and other 2'3'-cyclic dinucleotides. In contrast, LRRC8D inhibits cGAMP transport. We demonstrate that cGAMP is effluxed or influxed via LRRC8 channels, as dictated by the cGAMP electrochemical gradient. Activation of LRRC8A channels, which can occur under diverse stresses, strongly potentiates cGAMP transport. We identify activator sphingosine 1-phosphate and inhibitor DCPIB as chemical tools to manipulate channel-mediated cGAMP transport. Finally, LRRC8A channels are key cGAMP transporters in resting primary human vasculature cells and universal human cGAMP transporters when activated.

Topics: Biological Transport; CRISPR-Cas Systems; Cyclopentanes; Humans; Indans; Lysophospholipids; Membrane Proteins; Nucleotides, Cyclic; Sphingosine; U937 Cells