JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2021
·Vol. 25
·期 24
·11113-11127
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IF 5.31
Ting Liu,Shujia Chen,Xiaoli Xie,Hongqun Liu,Yongjuan Wang,Shengbin Qi,Linping Shi,Xue Zhou,Jiuna Zhang,Shuling Wang,Yijun Wang,Shengxiong Chen,Shiying Dou,Xiaoyu Jiang,Ruolin Cui,Huiqing Jiang
Triggering receptor expressed on myeloid cells-1 (TREM-1) exists in two forms: a transmembrane form and a soluble form (sTREM-1). The levels of sTREM-1 are elevated in supernatants of activated HSCs. However, the role of sTREM-1 in HSC activation and liver fibrosis remains undefined. Previous studies have primarily focused on the transmembrane form of TREM-1; we innovatively observed the function of sTREM-1 as a ligand in liver fibrosis and screened its receptor. Here, recombinant sTREM-1 was used as a stimulator which induced HSC activation and further aggravated liver fibrosis. Then, screening for sTREM-1 interacting membrane receptors was performed using pull-down assay followed by mass spectrometry, and the membrane receptor roundabout guidance receptor 2 (Robo2) was identified as a candidate receptor for sTREM-1. The interaction between sTREM-1 and Robo2 was verified by pull-down and immunofluorescence. The role of Robo2 on sTREM-1-induced HSC activation and its downstream signal pathways was assessed by knockdown of Robo2 in LX-2 cells. Furthermore, HSC-specific knockdown of Robo2 was achieved in a mouse model of liver fibrosis by using a recombinant adeno-associated virus (AAV) vector to confirm the role of the receptor, and we proved that Robo2 knockdown inhibited the activation of HSC and liver fibrosis, which also led to the inactivation of Smad2/3 and PI3K/Akt pathways in sTREM-1-induced HSC activation and liver fibrosis. In conclusion, sTREM-1 acts as a new ligand of Robo2; the binding of sTREM-1 to Robo2 initiates the activation of the downstream Smad2/3 and PI3K/Akt signalling pathways, thereby promoting HSC activation and liver fibrosis.
研究领域:
免疫学
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肝病学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2022
·
IF 5.714
Jian-Bing Xiong,Jia-Xi Duan,Nan Jiang,Chen-Yu Zhang,Wen-Jing Zhong,Jin-Tong Yang,Yu-Biao Liu,Feng Su,Yong Zhou,Dai Li,Hui-Hui Yang,Cha-Xiang Guan
Our previous study showed that triggering receptors expressed on myeloid cell-1 (TREM-1) was upregulated in bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model. However, the role of TREM-1 in the development of PF and its underlying mechanism remain unclear. Herein, we report that the prophylactical blockade of TREM-1 using a decoy peptide dodecapeptide (LR12) exerted protective effects against BLM-induced PF in mice, with a higher survival rate, attenuated tissue injury, and less extracellular matrix deposition. Interestingly, therapeutic blockade of TREM-1 at the early stage of fibrosis also attenuated BLM-induced PF, suggesting a non-inflammatory effect. More importantly, we observed that TREM-1 blockade with LR12 significantly reduced the expression of the senescence-relative protein, including p16, p21, p53, and γ-H2AX in the lungs of PF mice. Notably, TREM-1 was upregulated in alveolar epithelial cells (AECs) and correlated with the levels of senescence markers in BLM-treated mice. In vitro , activating TREM-1 with an agonistic antibody exacerbated BLM-induced senescence in MLE12 cells, a murine AEC cell line. Furthermore, prophylactic or therapeutic blockade of TREM-1 protected MLE12 cells from senescence induced by BLM or H 2 O 2 . In conclusion, our findings elucidate a pro-fibrotic effect of TREM-1 by inducing AECs senescence in PF, providing a potential strategy for fibrotic disease treatment.
研究领域:
肺科学
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免疫学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2024
·
IF 4.4
Xin Chen,Liming Yu,Shan Meng,Jikai Zhao,Xinyi Huang,Zhishang Wang,Zijun Zhou,Yuting Huang,Tao Hong,Jinfeng Duan,Tong Su,Zijun Cao,Yanbang Chi,Tao Huang,Huishan Wang
Inflammation and infiltration of immune cells are intricately linked to the pathogenesis of atrial fibrillation (AF). Triggering receptor expressed on myeloid cells-1 (TREM-1), an enhancer of inflammation, is implicated in various cardiovascular disorders. However, the precise role and potential mechanisms of TREM-1 in the development of AF remain ambiguous. Atrial samples from patients with AF were used to assess the expression levels of TREM-1. An angiotensin II (Ang II)-induced AF mouse model was established to assess the functionality of TREM-1. Cardiac function and AF inducibility were assessed through echocardiography, programmed transvenous cardiac pacing, and atrial electrophysiological mapping. Peripheral blood and atrial inflammatory cells were assessed using flow cytometry. Using histology, bulk RNA sequencing, biochemical analyses, and cell cultures, the mechanistic role of TREM-1 in AF was elucidated. TREM-1 expression was upregulated and co-localized with macrophages in the atria of patients with AF. Pharmacological inhibition of TREM-1 decreased Ang II-induced atrial enlargement and electrical remodeling. TREM-1 inhibition also ameliorated Ang II-induced NLRP3 inflammasome activation, inflammatory factor release, atrial fibrosis, and macrophage infiltration. Transcriptomic analysis revealed that TREM-1 modulates Ang II-induced inflammation through the PI3K/AKT/FoxO3a signaling pathway. In vitro studies further supported these findings, demonstrating that TREM-1 activation exacerbates Ang II-induced inflammation, while overexpression of FoxO3a counteracts this effect. This study discovered the critical role of TREM-1 in the pathogenesis of AF and its underlying molecular mechanisms. Inhibition of TREM-1 provides a new therapeutic strategy for the treatment of AF.
研究领域:
心脏病学
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免疫学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF HISTOCHEMISTRY
·
2024
·Vol. 68
·期 3
·4034
·
IF 2.1
Lan Wang,Zhenyu Fan,Haijin Wang,Shougui Xiang
Subarachnoid hemorrhage (SAH) is a devastating stroke caused by ruptured intracranial aneurysms, leading to blood accumulation around the brain. Early brain injury (EBI) within 72 h post-SAH worsens prognosis, primarily due to intense neuroinflammation. Microglia, pivotal in central nervous system defense and repair, undergo M1 to M2 polarization post-SAH, with M1 exacerbating neuroinflammation. Propofol (PPF), an anesthetic with anti-inflammatory properties, shows promise in mitigating neuroinflammation in SAH by modulating microglial activation. It likely acts through microRNAs like miR-140-5p, which attenuates microglial activation and inflammation by targeting TREM-1 and the NF-κB pathway. Understanding these mechanisms could lead to new therapeutic approaches for SAH-related EBI. In this study, BV-2 cell was used to establish in vitro model of SAH, and the expression of miR-140-5p and TREM-1 was detected after modeling. Microglial activity, apoptosis, the inflammatory pathway and response, oxidative damage, and M1/M2 polarization of microglia were evaluated by drug administration or transfection according to experimental groups. Finally, the targeting relationship between miR-140-5p and TREM-1 was verified by dual luciferase reporter assays, and the effect of PPF on the miR-140-5p/TREM-1/NF-κB signaling cascade was evaluated by RT ‒ qPCR or Western blotting. PPF effectively mitigates apoptosis, neuroinflammation, oxidative damage, and M1 microglial polarization in SAH. In SAH cells, PPF upregulates miR-140-5p and downregulates TREM-1. Mechanistically, PPF boosts miR-140-5p expression, while TREM-1, a downstream target of miR-140-5p, inhibits NF-κB signaling by regulating TREM-1, promoting M1 to M2 microglial polarization. Reduced miR-140-5p or increased TREM-1 counters PPF's therapeutic impact on SAH cells. In conclusion, PPF plays a neuroprotective role in SAH by regulating the miR-140-5p/TREM-1/NF-κB signaling axis to inhibit neuroinflammation and M1 polarization of microglia.
研究领域:
神经科学
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药理学
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炎症
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细胞生物学
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DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
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2022
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IF 2.65
Hong Zhang,Jian Ye,Xu Wang,Zongjun Liu,Tao Chen,Junqing Gao
The inhibitory effect of muscone on the hyperinflammatory response after myocardial ischemia reperfusion injury (MIRI) was investigated, and the target and signal pathways of muscone were explored. The levels of inflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor alpha were detected through qRT-PCR and ELISA. The expression levels of p38 and NF-κB signaling pathway-related proteins were detected through Western blot. TREM-1 siRNA was transfected into macrophages in vitro. The rat model of myocardial ischemia was established and used in studying the inhibitory effect of muscone on the inflammatory response and its protective effect muscone on myocardial apoptosis. The expression of TREM-1 was upregulated during myocardial ischemia. Knocking down TREM-1 decreased the increase in inflammatory cytokines in the supernatant of macrophages induced by rmHMGB1 (1 μg/mL) and rmHSP60 (1 mol/mL). In addition, knocking down TREM-1 decreased p38 and NF-κB signaling activation. Muscone can protect myocardial cells by inhibiting the expression of TREM-1 and the inflammatory response after myocardial infarction. Further study showed that muscone inhibited the production of DAM-triggered (damage-associated molecular pattern trigger) inflammatory cytokines. In addition, muscone inhibited the activation of p38 and NF-κB signals under DAM-induced conditions. Muscone and TREM-1 gene knockout reduced cell apoptosis and provided protection against MIRI by inhibiting p38 and NF-κB signaling activation. Mechanism studies showed that muscone inhibited the production and release of inflammatory cytokines by inhibiting TREM-1, and thereby reducing the inflammatory response and providing protection against MIRI.
研究领域:
心脏病学
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免疫学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
HISTOCHEMISTRY AND CELL BIOLOGY
·
2025
·Vol. 163
·期 1
·1-15
·
IF 2.1
Zhong Wen-Jing,Xiong Jian-Bing,Zhang Chen-Yu,Jin Ling,Yang Nan-Shi-Yu,Sha Han-Xi,Liu Yu-Biao,Duan Jia-Xi,Guan Cha-Xiang,Zhou Yong,Su Feng
Pulmonary fibrosis (PF) is an insidious, progressive, and fatal age-associated disease that occurs primarily in older adults and has a poor prognosis. Alveolar epithelial cell (AEC) senescence is the critical pathological mechanism of PF. The accumulation of oxygen radicals, commonly referred to as reactive oxygen species (ROS), strongly contributes to cellular senescence. The triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor. Triggering via TREM-1 results in ROS, leading to the amplification of inflammation. However, whether TREM-1 is involved in PF by inducing oxidative stress to exacerbate AEC senescence remains unclear. We first observed that blockade of TREM-1 during the fibrotic phase attenuated bleomycin (BLM)-induced PF in mice, with decreased expression of senescence-related proteins, including p16, p21, p53, and γ-H2AX, in the lung tissue. Moreover, TREM-1 blockade during the fibrosis stage restored antioxidant levels by increasing the percentage of Nrf2- and HO-1-positive cells in mice with PF. Notably, TREM-1 was highly expressed in surfactant-associated protein (SPC)-positive AECs in mice with PF. In vitro, blocking TREM-1 activated Nrf2 antioxidant signaling, thereby decreasing intracellular ROS levels and diminishing BLM-induced senescence in AECs. Furthermore, inhibition of Nrf2/HO-1 partially counteracted the anti-senescence effect of blocking TREM-1 in BLM-treated AECs. In this study, we reported that TREM-1 stimulated the senescence of AECs, induced ROS and exacerbated PF. We also provide compelling evidence suggesting that the Nrf2/HO-1 signaling pathway underpins TREM-1-triggered senescence. Therefore, our findings provide new insights into the molecular mechanisms associated with TREM-1 and AEC senescence in the pathogenesis of PF.
研究领域:
医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
RESPIRATORY RESEARCH
·
2023
·Vol. 24
·期 1
·1-19
·
IF 5.8
Liu Lin,Fan Haiyang,Li Liang,Fan Yunping
Background Type 2 diabetes mellitus (T2DM) is widely prevalent worldwide, and respiratory tract infections (RTIs) have become the primary cause of death for T2DM patients who develop concurrent infections. Among these, Pseudomonas aeruginosa infection has been found to exhibit a high mortality rate and poor prognosis and is frequently observed in bacterial infections that are concurrent with COVID-19. Studies have suggested that acarbose can be used to treat T2DM and reduce inflammation. Our objective was to explore the effect of acarbose on P. aeruginosa RTI in T2DM individuals and elucidate its underlying mechanism. Methods High-fat diet (HFD) induction and P. aeruginosa inhalation were used to establish a RTI model in T2DM mice. The effect and mechanism of acarbose administered by gavage on P. aeruginosa RTI were investigated in T2DM and nondiabetic mice using survival curves, pathological examination, and transcriptomics. Results We found that P. aeruginosa RTI was more severe in T2DM mice than in nondiabetic individuals, which could be attributed to the activation of the NF-κB and TREM-1 signaling pathways. When acarbose alleviated P. aeruginosa RTI in T2DM mice, both HIF-1α and NF-κB signaling pathways were inhibited. Furthermore, inhibition of the calcium ion signaling pathway and NF-κB signaling pathway contributed to the attenuation of P. aeruginosa RTI by acarbose in nondiabetic mice. Conclusions This study confirmed the attenuating effect of acarbose on P. aeruginosa RTIs in T2DM and nondiabetic mice and investigated its mechanism, providing novel support for its clinical application in related diseases.
研究领域:
药理学
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微生物学
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传染病学
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糖尿病学
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DOI
PubMed
高影响因子
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