title: RNY (YRNA)-derived small RNAs regulate cell death and inflammation in monocytes/macrophages.
abstract: The recent discovery of new classes of small RNAs has opened unknown territories to explore new regulations of physiopathological events. We have recently demonstrated that RNY (or Y RNA)-derived small RNAs (referred to as s-RNYs) are an independent class of clinical biomarkers to detect coronary artery lesions and are associated with atherosclerosis burden. Here, we have studied the role of s-RNYs in human and mouse monocytes/macrophages and have shown that in lipid-laden monocytes/macrophages s-RNY expression is timely correlated to the activation of both NF-κB and caspase 3-dependent cell death pathways. Loss- or gain-of-function experiments demonstrated that s-RNYs activate caspase 3 and NF-κB signaling pathways ultimately promoting cell death and inflammatory responses. As, in atherosclerosis, Ro60-associated s-RNYs generated by apoptotic macrophages are released in the blood of patients, we have investigated the extracellular function of the s-RNY/Ro60 complex. Our data demonstrated that s-RNY/Ro60 complex induces caspase 3-dependent cell death and NF-κB-dependent inflammation, when added to the medium of cultured monocytes/macrophages. Finally, we have shown that s-RNY function is mediated by Toll-like receptor 7 (TLR7). Indeed using chloroquine, which disrupts signaling of endosome-localized TLRs 3, 7, 8 and 9 or the more specific TLR7/9 antagonist, the phosphorothioated oligonucleotide IRS954, we blocked the effect of either intracellular or extracellular s-RNYs. These results position s-RNYs as relevant novel functional molecules that impacts on macrophage physiopathology, indicating their potential role as mediators of inflammatory diseases, such as atherosclerosis.
authors.affiliation: INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 10 'Control of Gene Expression', Nice, France.|University of Nice Sophia Antipolis, Faculty of Medicine, Nice, France.
authors.forename: Zoheir
authors.initials: Z
authors.lastname: Hizir
authors.affiliation: INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 10 'Control of Gene Expression', Nice, France.|University of Nice Sophia Antipolis, Faculty of Medicine, Nice, France.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bottini
authors.affiliation: INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 10 'Control of Gene Expression', Nice, France.|University of Nice Sophia Antipolis, Faculty of Medicine, Nice, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Grandjean
authors.affiliation: INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 10 'Control of Gene Expression', Nice, France.|University of Nice Sophia Antipolis, Faculty of Medicine, Nice, France.
authors.forename: Michele
authors.initials: M
authors.lastname: Trabucchi
authors.affiliation: INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 10 'Control of Gene Expression', Nice, France.|University of Nice Sophia Antipolis, Faculty of Medicine, Nice, France.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Repetto
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D020733:RNA, Small Cytoplasmic / Q000235:genetics* / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000235:genetics; D000099207:SS-A Antigen
chemical_list: D001324:Autoantigens; D053148:Caspase 3; D020733:RNA, Small Cytoplasmic; D012261:Ribonucleoproteins; D051199:Toll-Like Receptor 7; C116006:RO60 protein, human; D000099207:SS-A Antigen; C495348:TLR7 protein, human