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).

Macrophages: Their role, activation and polarization in pulmonary diseases

“…We have also demonstrated a novel nanomicellar (LP17 nanomedicine) approach to inhibit TREM-1 effects. Thus, our study suggests TREM-1 to be a potential therapeutic target for treatment of ARDS (Yuan et al, 2016).…”

Nanomedicine for Treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome

“…To effectively block the expression of TREM1, we developed LP17 peptide nanomedicine, LP17-SSM. LP17 is the soluble TREM1 or extracellular component which binds and inhibits signaling through TREM1 [5]. Control SSMs were prepared by using scrambled peptide.…”

“…Unfortunately, contemporary drug development approaches to address this challenge have not been rewarding -in particular blockade of single cytokines and chemokines have failed to show an improvement in outcomes because of the complex pathogenesis and nature of the disease [4]. Therefore, defining the contribution of proximal signaling pathways that amplify the inflammatory response and developing targeted therapies to specifically block them is an attractive approach to limit injury and inflammation for this devastating disease [5]. To this end, we have identified several targets that modulate signaling pathways that amplify inflammation and hence are attractive to be tested as potential therapies for ALI and ARDS.…”

“…Accordingly, we have harnessed unique attributes of 3 novel, long-acting, biocompatible, and biodegradable anti-inflammatory nanomedicines and tested them in cell and murine models of inflammation. They consist of 2 amphipathic peptide drugs, human glucagon-like peptide-1(7-36) amide (GLP-1), triggering receptor expressed on myeloid cells (TREM1) blocking peptide, and 17-allylamino-17-demethoxygeldanamycin (17-AAG), a water-insoluble cytotoxic drug [5,[16][17][18]. This innovative approach consists of selfassembly of each drug with US FDA-generally regarded-as-safe distearoylphosphatidylethanolamine covalently linked to polyethylene glycol of molecular weight 2,000 (DSPE-PEG 2000 ), a component of US FDA-approved Doxil ® , that forms long-acting, biocompatible and biodegradable, sterically stabilized phospholipid micelles in an aqueous milieu (SSM; size: ∼15 nm) [5,[17][18][19][20].…”

Reversal of TREM-1 ectodomain shedding and improved bacterial clearance by intranasal metalloproteinase inhibitors

“…4 TREM-1 signaling also enhances NF-kB induced cytokine production in dendritic cells via caspase-recruitment domain protein (CARD)-9 5 and downregulates suppressor of cytokine signaling-1 (SOCS-1) by inducing the expression of miR-155 in macrophages and lungs of mice treated with LPS. 6 Like many membrane bound receptors, TREM-1 also exists in soluble form (sTREM-1). Although the function of sTREM-1 is unknown, it is likely to negatively regulate membrane TREM-1 receptor signaling through competition with the ligand(s).…”