Soluble Epoxide Hydrolase Inhibitor Suppresses the Expression of Triggering Receptor Expressed on Myeloid Cells-1 by Inhibiting NF-kB Activation in Murine Macrophage

Abstract

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.

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

“…Depletion or blocking TREM-1 has shown protective effects in sepsis, ischemia-reperfusion, pancreatitis, inflammatory bowel diseases, Fungal Keratitis and arthritis14151617181920. 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 ALI2122. Although the pro-inflammatory effect of TREM-1 and its implication in the pathogenesis of inflammatory diseases are emerging, the mechanisms are still poorly understood.…”

Triggering receptor expressed on myeloid cells in the pathogenesis of periodontitis: potential novel treatment strategies

“…DAP12 is a transmembrane protein with an immunoreceptor tyrosine-based activation motif (ITAM) signaling unit [33]. TREM-1 consists of an extracellular domain, a transmembrane region, and a short cytoplasmic domain which lacks any signaling motifs [32].…”

“…The overarching goal of this research should be finding a way to use TREM receptors as interventional methods to reverse or arrest progression for periodontal diseases and systemic infections. There are several studied methods of TREM-1 manipulation, all of which could provide novel treatment methodologies for periodontal disease [17,21,27,33,53]. Synthetic TREM-1 blockade could mitigate the host inflammatory response and be useful as an adjunct therapy for the treatment of periodontal disease.…”

The phosphatase activity of soluble epoxide hydrolase regulates ATP‐binding cassette transporter‐A1‐dependent cholesterol efflux

“…The implication of hydrolase activity of sEH in the metabolism of epoxyeicosatrienoic acids (EETs), inflammation and hypertension has been well documented . For example, pharmacological inhibition of the EH activity of sEH or deletion of the sEH gene causes an increase in the accumulation of EETs and leads to the attenuation of angiotensin II–induced hypertension and cardiac hypertrophy and lipopolysaccharide‐induced inflammation in vitro and in vivo . Oral administration with inhibitors targeting EH activity of sEH or genetic disruption of sEH significantly retards the progression of atherosclerosis in hyperlipidemic mouse models .…”

“…causes an increase in the accumulation of EETs and leads to the attenuation of angiotensin II-induced hypertension and cardiac hypertrophy and lipopolysaccharide-induced inflammation in vitro and in vivo. [5][6][7][8] Oral administration with inhibitors targeting EH activity of sEH or genetic disruption of sEH significantly retards the progression of atherosclerosis in hyperlipidemic mouse models. 9,10 Multiple lines of evidence demonstrate that the PT domain of sEH also has a crucial role in the regulation of cholesterol metabolism and cell growth in hepatocytes.…”