title: TREM-1-accentuated lung injury via miR-155 is inhibited by LP17 nanomedicine.
abstract: Triggering receptors expressed on myeloid cell-1 (TREM-1) is a superimmunoglobulin receptor expressed on myeloid cells. Synergy between TREM-1 and Toll-like receptor amplifies the inflammatory response; however, the mechanisms by which TREM-1 accentuates inflammation are not fully understood. In this study, we investigated the role of TREM-1 in a model of LPS-induced lung injury and neutrophilic inflammation. We show that TREM-1 is induced in lungs of mice with LPS-induced acute neutrophilic inflammation. TREM-1 knockout mice showed an improved survival after lethal doses of LPS with an attenuated inflammatory response in the lungs. Deletion of TREM-1 gene resulted in significantly reduced neutrophils and proinflammatory cytokines and chemokines, particularly IL-1β, TNF-α, and IL-6. Physiologically deletion of TREM-1 conferred an immunometabolic advantage with low oxygen consumption rate (OCR) sparing the respiratory capacity of macrophages challenged with LPS. Furthermore, we show that TREM-1 deletion results in significant attenuation of expression of miR-155 in macrophages and lungs of mice treated with LPS. Experiments with antagomir-155 confirmed that TREM-1-mediated changes were indeed dependent on miR-155 and are mediated by downregulation of suppressor of cytokine signaling-1 (SOCS-1) a key miR-155 target. These data for the first time show that TREM-1 accentuates inflammatory response by inducing the expression of miR-155 in macrophages and suggest a novel mechanism by which TREM-1 signaling contributes to lung injury. Inhibition of TREM-1 using a nanomicellar approach resulted in ablation of neutrophilic inflammation suggesting that TREM-1 inhibition is a potential therapeutic target for neutrophilic lung inflammation and acute respiratory distress syndrome (ARDS).
authors.affiliation: Department of Veterans Affairs, Atlanta Veterans Affairs Medical Center, Decatur, Georgia; Division of Pulmonary and Critical Care Medicine, Emory University, Atlanta, Georgia;
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Division of Pulmonary and Critical Medicine, Yale University, New Haven, Connecticut;
authors.forename: Mansoor
authors.initials: M
authors.lastname: Syed
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Illinois at Chicago, Chicago, Illinois;
authors.forename: Dipti
authors.initials: D
authors.lastname: Panchal
authors.affiliation: Department of Immunology, Pusan University, Yangsan, Korea;
authors.forename: Myungsoo
authors.initials: M
authors.lastname: Joo
authors.affiliation: Department of Veterans Affairs, Atlanta Veterans Affairs Medical Center, Decatur, Georgia;
authors.forename: Chetna
authors.initials: C
authors.lastname: Bedi
authors.affiliation: School of Pharmacy, University of Illinois at Chicago, Chicago, Illinois;
authors.forename: Sokbee
authors.initials: S
authors.lastname: Lim
authors.affiliation: School of Pharmacy, University of Illinois at Chicago, Chicago, Illinois;
authors.forename: Hayat
authors.initials: H
authors.lastname: Onyuksel
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Illinois at Chicago, Chicago, Illinois; Department of Veterans Affairs, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois; and.
authors.forename: Israel
authors.initials: I
authors.lastname: Rubinstein
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.affiliation: Department of Veterans Affairs, Atlanta Veterans Affairs Medical Center, Decatur, Georgia; Division of Pulmonary and Critical Care Medicine, Emory University, Atlanta, Georgia; Ruxana.Sadikot@emory.edu.
authors.forename: Ruxana T
authors.initials: RT
authors.lastname: Sadikot
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D055370:Lung Injury / Q000188:drug therapy* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism; D050997:Nanomedicine / Q000379:methods; D034741:RNA, Small Interfering / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; C517262:TREM1 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
keywords: TREM-1; lung injury; miR-155; nanomedicine