Blocking triggering receptor expressed on myeloid cells-1 attenuates lipopolysaccharide-induced acute lung injury via inhibiting NLRP3 inflammasome activation.

Tian Liu,Guo-Ying Sun,Xiang Fang,Jia-Xi Duan,Liang Dong,Jian-Xin Jiang,Li Wan,Yong Zhou,Yong-Ping Liu,Ping Li,Cha-Xiang Guan

doi:10.1038/srep39473

Abstract

Acute lung injury (ALI) is associated with high mortality and uncontrolled inflammation plays a critical role in ALI. TREM-1 is an amplifier of inflammatory response, and is involved in the pathogenesis of many infectious diseases. NLRP3 inflammasome is a member of NLRs family that contributes to ALI. However, the effect of TREM-1 on NLRP3 inflammasome and ALI is still unknown. This study aimed to determine the effect of TREM-1 modulation on LPS-induced ALI and activation of the NLRP3 inflammasome. We showed that LR12, a TREM-1 antagonist peptide, significantly improved survival of mice after lethal doses of LPS. LR12 also attenuated inflammation and lung tissue damage by reducing histopathologic changes, infiltration of the macrophage and neutrophil into the lung, and production of the pro-inflammatory cytokine, and oxidative stress. LR12 decreased expression of the NLRP3, pro-caspase-1 and pro-IL-1β, and inhibited priming of the NLRP3 inflammasome by inhibiting NF-κB. LR12 also reduced the expression of NLRP3 and caspase-1 p10 protein, and secretion of the IL-1β, inhibited activation of the NLRP3 inflammasome by decreasing ROS. For the first time, these data show that TREM-1 aggravates inflammation in ALI by activating NLRP3 inflammasome, and blocking TREM-1 may be a potential therapeutic approach for ALI.

Highlights

The Nod-like receptors (NLRs) family, pyrin domain containing 3 (NLRP3) inflammasome, is comprised of NLRP3, the adaptor protein apoptosis associated speck like protein (ASC) and pro-caspase-1
Our preliminary experiments showed that either antagonistic Triggering receptors expressed on myeloid cell-1 (TREM-1) peptide (LR12) or sequence-scrambled control peptide (LRS) alone did not alter morphological characteristics, pro-inflammatory cytokine expression and cellular damage of lung in the mice treated with normal saline (Fig. s1)
To determine the protective effects of TREM-1 inhibition on LPS-induced Acute lung injury (ALI), we investigated whether LR12 (5 mg/kg, i.v.) could improve survival in ALI mice induced by a lethal dose of LPS (20 mg/kg, i.t)

Summary

Introduction

The NLRs family, pyrin domain containing 3 (NLRP3) inflammasome, is comprised of NLRP3, the adaptor protein apoptosis associated speck like protein (ASC) and pro-caspase-1. NLRP3 inflammasome activates caspase-1, which processes precursor form of cytokines (pro-IL-1βand pro-IL-18) to their mature biologically active and secreted forms (IL-1βand IL-18) These bioactive cytokines play a pivotal role in initiation and amplification of the inflammatory processes of ALI. Our previous study found that the expression of TREM-1 in LPS-induced ALI mice lung and macrophages are significantly increased, suggesting an important role of TREM-1 in ALI21,22. Previous study showed that TREM-1 activation can increase LPS-induced IL-1βproduction in human monocytes[23], suggesting a regulatory role of TREM-1 in activation of the NLRP3 inflammasome. A 12 amino acid antagonistic polypeptide (LR12, LQEEDTGEYGCV) derived from mouse TLT-1 was synthesized to investigate the role of TREM-1 in ALI and NLRP3 activation. The protective effects by LR12 may be related to inhibition of NF-κB activation and ROS production

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Conclusion