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-1ß, 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).
Subject(s)
Lung Injury/drug therapy , Macrophages/drug effects , Membrane Glycoproteins/metabolism , MicroRNAs/genetics , Receptors, Immunologic/metabolism , Animals , Cytokines/metabolism , Inflammation/metabolism , Lipopolysaccharides/pharmacology , Lung Injury/metabolism , Macrophages/metabolism , Male , Mice, Inbred C57BL , Myeloid Cells/drug effects , Myeloid Cells/metabolism , Nanomedicine/methods , RNA, Small Interfering/metabolism , Triggering Receptor Expressed on Myeloid Cells-1ABSTRACT
As congenital hearing impairment has a worldwide incidence of 4 to 5 per 1000 babies and is thus one of the most common congenital problems seen today, universal newborn screening has a crucial role to play in its early detection and intervention. It provides the opportunity for better outcomes and normal language development. Prior to embarking on a screening programme, the newborn population and the current health care system should be analysed to select the best method of coverage. The screening tool and protocol, communication of results, as well as the follow-up measures should be clearly determined and tested. The multidisciplinary team required should be provided with the necessary information. Parents need to be educated about the importance of early hearing screening. Data management and surveillance should be established in a systematic manner. The costs of the programme should be carefully anticipated and funding sources determined. Finally, support for the programme should be sought from governmental or public health bodies, to ensure the success of the programme. Legislation can be considered if necessary.
Subject(s)
Hearing Tests , Neonatal Screening/organization & administration , Humans , Infant, Newborn , Program DevelopmentABSTRACT
Soy supplements are often consumed by women for alleviating menopausal symptoms or for the perceived protective effects against breast cancer. More concerning is the concurrent consumption of soy isoflavones with tamoxifen (TAM) for prevention or treatment of breast cancer. We previously described a T47D:A18/protein kinase C (PKC)alpha TAM-resistant tumor model that exhibits autonomous growth and estradiol-induced tumor regression. We compared the estrogenicity of the isoflavones genistein, daidzein, and the daidzein metabolite equol in the parental T47D:A18 and T47D:A18/PKC alpha cell lines in vitro and in vivo. Whereas equol exerts estrogenic effects on T47D:A18 cells in vitro, none of the isoflavones stimulated T47D:A18 tumor growth. T47D:A18/PKC alpha tumor growth was partially stimulated by genistein, yet partially inhibited by daidzein. Interestingly, coadministration of TAM with either daidzein or genistein produced tumors of greater size than with TAM alone. These findings suggest that simultaneous consumption of isoflavone supplements with TAM may not be safe.
