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.

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Triggering receptors expressed on myeloid cell-1 (TREM-1) is a superimmunoglobulin receptor expressed on myeloid cells. TREM-1 amplifies the inflammatory response. Epoxyeicosatrienoic acids (EETs), the metabolites of arachidonic acid derived from the cytochrome P450 enzyme, have anti-inflammatory properties. However, the effects of EETs on TREM-1 expression under inflammatory stimulation remain unclear. Therefore, inhibition of soluble epoxide hydrolase (sEH) with a highly selective inhibitor [1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea, TPPU] was used to stabilize EETs. LPS was intratracheally injected into mice to induce pulmonary inflammation, after TPPU treatment for 3 h. Histological examination showed TPPU treatment-alleviated LPS-induced pulmonary inflammation. TPPU decreased TREM-1 expression, but not DAP12 or MyD88 expression. Murine peritoneal macrophages were challenged with LPS in vitro. We found that TPPU reduced LPS-induced TREM-1 expression in a dose-dependent manner, but not DAP12 or MyD88 expression. TPPU also decreased downstream signal from TREM-1, reducing pro-inflammatory cytokine TNF-α and IL-1β mRNA expression. Furthermore, TPPU treatment inhibited IkB degradation in vivo and in vitro. Our results indicate that the inhibition of sEH suppresses LPS-induced TREM-1 expression and inflammation via inhibiting NF-kB activation in murine macrophage.

A full understanding of the mechanisms behind spinal cord injury (SCI) processes requires reliable three-dimensional (3D) imaging tools for a thorough analysis of changes in angiospatial architecture. We aimed to use synchrotron radiation μCT (SRμCT) to characterize 3D temporal-spatial changes in microvasculature post-SCI. Morphometrical measurements revealed a significant decrease in vascular volume fraction, vascular bifurcation density, vascular segment density, and vascular connectivity density 1 day post-injury, followed by a gradual increase at 3, 7, and 14 days. At 1 day post-injury, SRμCT revealed an increase in vascular tortuosity (VT), which reached a plateau after 7 days and decreased slightly during the healing process. In addition, SRμCT images showed that vessels were largely concentrated in the gray matter 1 day post-injury. The maximal endothelial cell proliferation rate was detected at 7 days post-injury. The 3D morphology of the cavity appears in the spinal cord at 28 days post-injury. We describe a methodology for 3D analysis of vascular repair in SCI and reveal that endogenous revascularization occurs during the healing process. The spinal cord microvasculature configuration undergoes 3D remodeling and modification during the post-injury repair process. Examination of these processes might contribute to a full understanding of the compensatory vascular mechanisms after injury and aid in the development of novel and effective treatment for SCI.