TREM-1-accentuated lung injury via miR-155 is inhibited by LP17 nanomedicine

Zhihong Yuan, Mansoor Syed, Dipti Panchal, Myungsoo Joo, Chetna Bedi, Sokbee Lim, Hayat Onyuksel, Israel Rubinstein, Marco Colonna, Ruxana T. Sadikot

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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).

Original languageEnglish
Pages (from-to)L426-L438
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume310
Issue number5
DOIs
StatePublished - Mar 1 2016

Keywords

  • Lung injury
  • MiR-155
  • Nanomedicine
  • TREM-1

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