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Rapid neutrophil mobilisation by VCAM-1+ endothelial extracellular vesicles

Akbar, Naveed; Braithwaite, Adam T; Corr, Emma M; Koelwyn, Graeme J; van Solingen, Coen; Cochain, Clément; Saliba, Antoine-Emmanuel; Corbin, Alastair; Pezzolla, Daniela; Møller Jørgensen, Malene; Bæk, Rikke; Edgar, Laurienne; De Villiers, Carla; Gunadasa-Rohling, Mala; Banerjee, Abhirup; Paget, Daan; Lee, Charlotte; Hogg, Eleanor; Costin, Adam; Dhaliwal, Raman; Johnson, Errin; Krausgruber, Thomas; Riepsaame, Joey; Melling, Genevieve E; Shanmuganathan, Mayooran; Bock, Christoph; Carter, David R F; Channon, Keith M; Riley, Paul R; Udalova, Irina A; Moore, Kathryn J; Anthony, Daniel; Choudhury, Robin P
AIMS/OBJECTIVE:Acute myocardial infarction rapidly increases blood neutrophils (<2 hours). Release from bone marrow, in response to chemokine elevation, has been considered their source, but chemokine levels peak up to 24 hours after injury, and after neutrophil elevation. This suggests that additional non-chemokine-dependent processes may be involved. Endothelial cell (EC) activation promotes the rapid (<30 minutes) release of extracellular vesicles (EVs), which have emerged as an important means of cell-cell signalling and are thus a potential mechanism for communicating with remote tissues. METHODS AND RESULTS/RESULTS:Here, we show that injury to the myocardium rapidly mobilises neutrophils from the spleen to peripheral blood and induces their transcriptional activation prior to arrival at the injured tissue. Time course analysis of plasma EV composition revealed a rapid and selective increase in EVs bearing VCAM-1. These EVs, which were also enriched for miRNA-126, accumulated preferentially in the spleen where they induced local inflammatory gene and chemokine protein expression, and mobilised splenic-neutrophils to peripheral blood. Using CRISPR/Cas9 genome editing we generated VCAM-1-deficient EC-EVs and showed that its deletion removed the ability of EC-EVs to provoke the mobilisation of neutrophils. Furthermore, inhibition of miRNA-126 in vivo reduced myocardial infarction size in a mouse model. CONCLUSIONS:Our findings show a novel EV-dependent mechanism for the rapid mobilisation of neutrophils to peripheral blood from a splenic reserve and establish a proof of concept for functional manipulation of EV-communications through genetic alteration of parent cells. TRANSLATIONAL PERSPECTIVE/UNASSIGNED:Peripheral blood neutrophils are rapidly elevated following acute myocardial infarction (AMI) and prior to alterations in systemic cytokines. Extracellular vesicles (EVs) are membrane enclosed particles that carry protein and miRNAs and are rapidly liberated from endothelial cells (EC). Here, we show that following AMI EC-derived-EVs (EC-EVs) mediate neutrophil mobilisation from the spleen via EC-EV-VCAM-1 and induce transcriptional activation of neutrophils in the blood to favour miRNA-126-mRNA targets; miRNA-126 antagomir treatment lowers infarct size. EC-EV-VCAM-1 and EC-EV-miRNA-126 are novel mechanisms that mobilise splenic reserve of neutrophils, a previously unidentified source of neutrophils in sterile ischaemic injury.
PMID: 35134856
ISSN: 1755-3245
CID: 5156322

Long non-coding RNAs: definitions, functions, challenges and recommendations

Mattick, John S; Amaral, Paulo P; Carninci, Piero; Carpenter, Susan; Chang, Howard Y; Chen, Ling-Ling; Chen, Runsheng; Dean, Caroline; Dinger, Marcel E; Fitzgerald, Katherine A; Gingeras, Thomas R; Guttman, Mitchell; Hirose, Tetsuro; Huarte, Maite; Johnson, Rory; Kanduri, Chandrasekhar; Kapranov, Philipp; Lawrence, Jeanne B; Lee, Jeannie T; Mendell, Joshua T; Mercer, Timothy R; Moore, Kathryn J; Nakagawa, Shinichi; Rinn, John L; Spector, David L; Ulitsky, Igor; Wan, Yue; Wilusz, Jeremy E; Wu, Mian
Genes specifying long non-coding RNAs (lncRNAs) occupy a large fraction of the genomes of complex organisms. The term 'lncRNAs' encompasses RNA polymerase I (Pol I), Pol II and Pol III transcribed RNAs, and RNAs from processed introns. The various functions of lncRNAs and their many isoforms and interleaved relationships with other genes make lncRNA classification and annotation difficult. Most lncRNAs evolve more rapidly than protein-coding sequences, are cell type specific and regulate many aspects of cell differentiation and development and other physiological processes. Many lncRNAs associate with chromatin-modifying complexes, are transcribed from enhancers and nucleate phase separation of nuclear condensates and domains, indicating an intimate link between lncRNA expression and the spatial control of gene expression during development. lncRNAs also have important roles in the cytoplasm and beyond, including in the regulation of translation, metabolism and signalling. lncRNAs often have a modular structure and are rich in repeats, which are increasingly being shown to be relevant to their function. In this Consensus Statement, we address the definition and nomenclature of lncRNAs and their conservation, expression, phenotypic visibility, structure and functions. We also discuss research challenges and provide recommendations to advance the understanding of the roles of lncRNAs in development, cell biology and disease.
PMID: 36596869
ISSN: 1471-0080
CID: 5409912

Long noncoding RNA CHROMR regulates antiviral immunity in humans

van Solingen, Coen; Cyr, Yannick; Scacalossi, Kaitlyn R; de Vries, Maren; Barrett, Tessa J; de Jong, Annika; Gourvest, Morgane; Zhang, Tracy; Peled, Daniel; Kher, Raadhika; Cornwell, MacIntosh; Gildea, Michael A; Brown, Emily J; Fanucchi, Stephanie; Mhlanga, Musa M; Berger, Jeffrey S; Dittmann, Meike; Moore, Kathryn J
Long noncoding RNAs (lncRNAs) have emerged as critical regulators of gene expression, yet their contribution to immune regulation in humans remains poorly understood. Here, we report that the primate-specific lncRNA CHROMR is induced by influenza A virus and SARS-CoV-2 infection and coordinates the expression of interferon-stimulated genes (ISGs) that execute antiviral responses. CHROMR depletion in human macrophages reduces histone acetylation at regulatory regions of ISG loci and attenuates ISG expression in response to microbial stimuli. Mechanistically, we show that CHROMR sequesters the interferon regulatory factor (IRF)-2-dependent transcriptional corepressor IRF2BP2, thereby licensing IRF-dependent signaling and transcription of the ISG network. Consequently, CHROMR expression is essential to restrict viral infection of macrophages. Our findings identify CHROMR as a key arbitrator of antiviral innate immune signaling in humans.
PMID: 36001732
ISSN: 1091-6490
CID: 5331652

The Liver X Receptor Is Selectively Modulated to Differentially Alter Female Mammary Metastasis-associated Myeloid Cells

Ma, Liqian; Vidana Gamage, Hashni Epa; Tiwari, Srishti; Han, Chaeyeon; Henn, Madeline A; Krawczynska, Natalia; Dibaeinia, Payam; Koelwyn, Graeme J; Das Gupta, Anasuya; Bautista Rivas, Rafael Ovidio; Wright, Chris L; Xu, Fangxiu; Moore, Kathryn J; Sinha, Saurabh; Nelson, Erik R
Dysregulation of cholesterol homeostasis is associated with many diseases such as cardiovascular disease and cancer. Liver X receptors (LXRs) are major upstream regulators of cholesterol homeostasis and are activated by endogenous cholesterol metabolites such as 27-hydroxycholesterol (27HC). LXRs and various LXR ligands such as 27HC have been described to influence several extra-hepatic biological systems. However, disparate reports of LXR function have emerged, especially with respect to immunology and cancer biology. This would suggest that, similar to steroid nuclear receptors, the LXRs can be selectively modulated by different ligands. Here, we use RNA-sequencing of macrophages and single-cell RNA-sequencing of immune cells from metastasis-bearing murine lungs to provide evidence that LXR satisfies the 2 principles of selective nuclear receptor modulation: (1) different LXR ligands result in overlapping but distinct gene expression profiles within the same cell type, and (2) the same LXR ligands differentially regulate gene expression in a highly context-specific manner, depending on the cell or tissue type. The concept that the LXRs can be selectively modulated provides the foundation for developing precision pharmacology LXR ligands that are tailored to promote those activities that are desirable (proimmune), but at the same time minimizing harmful side effects (such as elevated triglyceride levels).
PMID: 35569056
ISSN: 1945-7170
CID: 5249112

Advancing therapeutic targeting of the vulnerable plaque [Comment]

Newman, Alexandra A C; Cyr, Yannick; Moore, Kathryn J
PMID: 35567566
ISSN: 1522-9645
CID: 5215162

Rapid neutrophil mobilization by VCAM-1+endothelial cell-derived extracellular vesicles

Akbar, Naveed; Braithwaite, Adam T.; Corr, Emma M.; Koelwyn, Graeme J.; van Solingen, Coen; Cochain, Clement; Saliba, Antoine-Emmanuel; Corbin, Alastair; Pezzolla, Daniela; Jorgensen, Malene Moller; Baek, Rikke; Edgar, Laurienne; De Villiers, Carla; Gunadasa-Rohling, Mala; Banerjee, Abhirup; Paget, Daan; Lee, Charlotte; Hogg, Eleanor; Costin, Adam; Dhaliwal, Raman; Johnson, Errin; Krausgruber, Thomas; Riepsaame, Joey; Melling, Genevieve E.; Shanmuganathan, Mayooran; Bock, Christoph; Carter, David R. F.; Channon, Keith M.; Riley, Paul R.; Udalova, Irina A.; Moore, Kathryn J.; Anthony, Daniel; Choudhury, Robin P.
ISSN: 0008-6363
CID: 5182682

Two birds, one stone: NFATc3 controls dual actions of miR-204 in foam cell formation [Comment]

van Solingen, Coen; Moore, Kathryn J
PMID: 34571536
ISSN: 1522-9645
CID: 5107772

Reverse cardio-oncology: Exploring the effects of cardiovascular disease on cancer pathogenesis

Koelwyn, Graeme J; Aboumsallem, Joseph Pierre; Moore, Kathryn J; de Boer, Rudolf A
The field of cardio-oncology has emerged in response to the increased risk of cardiovascular disease (CVD) in patients with cancer. However, recent studies suggest a more complicated CVD-cancer relationship, wherein development of CVD, either prior to or following a cancer diagnosis, can also lead to increased risk of cancer and worse outcomes for patients. In this review, we describe the current evidence base, across epidemiological as well as preclinical studies, which supports the emerging concept of 'reverse-cardio oncology', or CVD-induced acceleration of cancer pathogenesis.
PMID: 34582824
ISSN: 1095-8584
CID: 5061632

Chronic stress primes innate immune responses in mice and humans

Barrett, Tessa J; Corr, Emma M; van Solingen, Coen; Schlamp, Florencia; Brown, Emily J; Koelwyn, Graeme J; Lee, Angela H; Shanley, Lianne C; Spruill, Tanya M; Bozal, Fazli; de Jong, Annika; Newman, Alexandra A C; Drenkova, Kamelia; Silvestro, Michele; Ramkhelawon, Bhama; Reynolds, Harmony R; Hochman, Judith S; Nahrendorf, Matthias; Swirski, Filip K; Fisher, Edward A; Berger, Jeffrey S; Moore, Kathryn J
Psychological stress (PS) is associated with systemic inflammation and accelerates inflammatory disease progression (e.g., atherosclerosis). The mechanisms underlying stress-mediated inflammation and future health risk are poorly understood. Monocytes are key in sustaining systemic inflammation, and recent studies demonstrate that they maintain the memory of inflammatory insults, leading to a heightened inflammatory response upon rechallenge. We show that PS induces remodeling of the chromatin landscape and transcriptomic reprogramming of monocytes, skewing them to a primed hyperinflammatory phenotype. Monocytes from stressed mice and humans exhibit a characteristic inflammatory transcriptomic signature and are hyperresponsive upon stimulation with Toll-like receptor ligands. RNA and ATAC sequencing reveal that monocytes from stressed mice and humans exhibit activation of metabolic pathways (mTOR and PI3K) and reduced chromatin accessibility at mitochondrial respiration-associated loci. Collectively, our findings suggest that PS primes the reprogramming of myeloid cells to a hyperresponsive inflammatory state, which may explain how PS confers inflammatory disease risk.
PMID: 34496250
ISSN: 2211-1247
CID: 5012012

Silencing Myeloid Netrin-1 Induces Inflammation Resolution and Plaque Regression

Schlegel, Martin Paul; Sharma, Monika; Brown, Emily J; Newman, Alexandra Ac; Cyr, Yannick; Afonso, Milessa Silva; Corr, Emma M; Koelwyn, Graeme J; van Solingen, Coen; Guzman, Jonathan; Farhat, Rubab; Nikain, Cyrus A; Shanley, Lianne C; Peled, Daniel; Schmidt, Ann Marie; Fisher, Edward A; Moore, Kathryn J
PMID: 34289717
ISSN: 1524-4571
CID: 4948372