RÉSUMÉ
Triggering receptor expressed on myeloid cells 1 (TREM1) is a cell surface receptor expressed on neutrophils, monocytes and some tissue macrophages, where it functions as an immunoregulator that controls myeloid cell responses. The activation of TREM1 is suggested to be an upregulation-based, ligands-induced and structural multimerization-mediated process, in which damage- and pathogen-associated molecular patterns play important roles. Activated TREM1 initiates an array of downstream signaling pathways that ultimately result in the production of pro-inflammatory cytokines and chemokines, whereby it functions as an amplifier of inflammation and is implicated in the pathogenesis of many inflammation-associated diseases. Over the past decade, there has been growing evidence for the involvement of TREM1 overactivation in tumor stroma inflammation and cancer progression. Indeed, it was shown that TREM1 promotes tumor progression, immunosuppression, and resistance to therapy by activating tumor-infiltrating myeloid cells. TREM1-deficiency or blockade provide protection against tumors and reverse the resistance to anti-PD-1/PD-L1 therapy and arginine-deprivation therapy in preclinical models. Here, we first review the structure, activation modes and signaling pathways of TREM1 and emphasize the role of soluble TREM1 as a biomarker of infection and cancer. We then focus on the role of TREM1 in cancer and systematically summarize its expression patterns, upregulation mechanisms and functions in tumor development and progression. Lastly, we discuss the therapeutic prospects of TREM1 inhibition, via effective pharmacological inhibitors, in treating cancer and other diseases.
Sujet(s)
Tumeurs , Transduction du signal , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/métabolisme , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteurs , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/génétique , Humains , Tumeurs/métabolisme , Tumeurs/traitement médicamenteux , Tumeurs/immunologie , Tumeurs/génétique , Tumeurs/anatomopathologie , Animaux , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/pharmacologieRÉSUMÉ
BACKGROUND: Traumatic brain injury (TBI), as a major public health problem, is characterized by high incidence rate, disability rate, and mortality rate. Neuroinflammation plays a crucial role in the pathogenesis of TBI. Triggering receptor expressed on myeloid cells-1 (TREM-1) is recognized as an amplifier of the inflammation in diseases of the central nervous system (CNS). However, the function of TREM-1 remains unclear post-TBI. This study aimed to investigate the function of TREM-1 in neuroinflammation induced by TBI. METHODS: Brain water content (BWC), modified neurological severity score (mNSS), and Morris Water Maze (MWM) were measured to evaluate the effect of TREM-1 inhibition on nervous system function and outcome after TBI. TREM-1 expression in vivo was evaluated by Western blotting. The cellular localization of TREM-1 in the damaged region was observed via immunofluorescence staining. We also conducted Western blotting to examine expression of SYK, p-SYK and other downstream proteins. RESULTS: We found that inhibition of TREM-1 reduced brain edema, decreased mNSS and improved neurobehavioral outcomes after TBI. It was further determined that TREM-1 was expressed on microglia and modulated subtype transition of microglia. Inhibition of TREM-1 alleviated neuroinflammation, which was associated with SYK/p38MAPK signaling pathway. CONCLUSIONS: These findings suggest that TREM-1 can be a potential clinical therapeutic target for alleviating neuroinflammation after TBI.
Sujet(s)
Lésions traumatiques de l'encéphale , Microglie , Maladies neuro-inflammatoires , Syk kinase , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes , p38 Mitogen-Activated Protein Kinases , Lésions traumatiques de l'encéphale/métabolisme , Lésions traumatiques de l'encéphale/traitement médicamenteux , Animaux , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/métabolisme , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteurs , Microglie/métabolisme , Microglie/effets des médicaments et des substances chimiques , Syk kinase/métabolisme , Syk kinase/antagonistes et inhibiteurs , Mâle , Maladies neuro-inflammatoires/métabolisme , Maladies neuro-inflammatoires/traitement médicamenteux , p38 Mitogen-Activated Protein Kinases/métabolisme , Souris , Transduction du signal/effets des médicaments et des substances chimiques , Oedème cérébral/métabolisme , Oedème cérébral/traitement médicamenteux , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Système de signalisation des MAP kinases/physiologie , Souris de lignée C57BLRÉSUMÉ
Sepsis often causes cell death via pyroptosis and hence results in septic cardiomyopathy. Triggering receptors expressed in myeloid cells-1 (TREM-1) may initiate cellular cascade pathways and, in turn, induce cell death and vital organ dysfunction in sepsis, but the evidence is limited. We set to investigate the role of TREM-1 on nucleotide-binding oligomerization domain-like receptors with pyrin domain-3 (NLRP3) inflammasome activation and cardiomyocyte pyroptosis in sepsis models using cardiac cell line (HL-1) and mice. In this study, TREM-1 was found to be significantly increased in HL-1 cells challenged with lipopolysaccharide (LPS). Pyroptosis was also significantly increased in the HL-1 cells challenged with lipopolysaccharide and an NLRP3 inflammasome activator, nigericin. The close interaction between TREM-1 and structural maintenance of chromosome 4 (SMC4) was also identified. Furthermore, inhibition of TREM-1 or SMC4 prevented the upregulation of NLRP3 and decreased Gasdermin-D, IL-1ß and caspase-1 cleavage. In mice subjected to caecal ligation and puncture, the TREM-1 inhibitor LR12 decreased the expression of NLRP3 and attenuated cardiomyocyte pyroptosis, leading to improved cardiac function and prolonged survival of septic mice. Our work demonstrates that, under septic conditions, TREM-1 plays a critical role in cardiomyocyte pyroptosis. Targeting TREM-1 and its associated molecules may therefore lead to novel therapeutic treatments for septic cardiomyopathy.
Sujet(s)
Inflammasomes , Myocytes cardiaques , Protéine-3 de la famille des NLR contenant un domaine pyrine , Pyroptose , Sepsie , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes , Animaux , Humains , Souris , Adenosine triphosphatases/immunologie , Cardiomyopathies/étiologie , Cardiomyopathies/génétique , Cardiomyopathies/immunologie , Caspase-1/génétique , Protéines chromosomiques nonhistones/génétique , Protéines chromosomiques nonhistones/immunologie , Chromosomes humains de la paire 4/immunologie , Inflammasomes/agonistes , Inflammasomes/génétique , Inflammasomes/immunologie , Lipopolysaccharides/effets indésirables , Lipopolysaccharides/pharmacologie , Cellules myéloïdes/immunologie , Myocytes cardiaques/immunologie , Protéine-3 de la famille des NLR contenant un domaine pyrine/agonistes , Protéine-3 de la famille des NLR contenant un domaine pyrine/génétique , Protéine-3 de la famille des NLR contenant un domaine pyrine/immunologie , Pyroptose/génétique , Pyroptose/immunologie , Sepsie/complications , Sepsie/génétique , Sepsie/immunologie , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteurs , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/génétique , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/immunologieRÉSUMÉ
BACKGROUND: Extracellular cold-inducible RNA-binding protein aggravates acute kidney injury after renal ischemia/reperfusion. Although extracellular cold-inducible RNA-binding protein activates triggering receptor expressed on myeloid cells-1, how this receptor and its antagonism with a novel peptide M3 affects acute kidney injury is poorly understood. We, therefore, hypothesize that inhibiting the extracellular cold-inducible RNA-binding protein/triggering receptor expressed on myeloid cells-1 pathway with M3 attenuates acute kidney injury. METHODS: Wild-type and triggering receptor expressed on myeloid cells-1-/- mice were subjected to bilateral 30-minute renal hilum clamping followed by reperfusion or sham. After 4 hours, wild-type mice received M3 (10 mg/kg BW) or normal saline intraperitoneally. After 24 hours, renal tissue and serum were collected for analysis. Additionally, wild-type mice were subjected to bilateral renal ischemia for 34 minutes and treated with M3 at 10 mg/kg BW or vehicle at the time of reperfusion. Survival was monitored for 10 days. RESULTS: After renal ischemia/reperfusion, triggering receptor expressed on myeloid cells-1 messenger ribonucleic acid expression increased by 9-fold in wild-type mice compared to sham mice. Wild-type mice also demonstrated significant increases in serum blood urea nitrogen, creatinine, and interleukin-6 and renal tissue levels of interleukin-6 and neutrophil gelatinase-associated lipocalin after renal ischemia/reperfusion compared to sham mice. Triggering receptor expressed on myeloid cells-1-/- mice demonstrated significant reductions in serum blood urea nitrogen, creatinine, and interleukin-6 compared to wild-type mice after renal ischemia/reperfusion. Levels of renal interleukin-6 and neutrophil gelatinase-associated lipocalin were also significantly decreased in the kidneys of triggering receptor expressed on myeloid cells-1-/- mice. Furthermore, treatment with M3 in wild-type mice significantly decreased serum and renal levels of interleukin-6 after renal ischemia/reperfusion. M3 treatment demonstrated significant reductions in renal messenger ribonucleic acid and protein levels of neutrophil gelatinase-associated lipocalin, serum blood urea nitrogen and creatinine, and histologic structural damage as well as apoptosis. Treatment with M3 also increased survival from 35% to 65% in mice with acute kidney injury. CONCLUSION: Triggering receptor expressed on myeloid cells-1 mediates the deleterious effects of extracellular cold-inducible RNA-binding protein in acute kidney injury after renal ischemia/reperfusion. The novel extracellular cold-inducible RNA-binding protein/triggering receptor expressed on myeloid cells-1 pathway antagonist, M3, attenuates acute kidney injury and has the potential to be developed as a therapeutic agent for acute kidney injury.
Sujet(s)
Atteinte rénale aigüe , Lésion d'ischémie-reperfusion , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes , Atteinte rénale aigüe/traitement médicamenteux , Atteinte rénale aigüe/étiologie , Atteinte rénale aigüe/prévention et contrôle , Animaux , Créatinine , Interleukine-6/métabolisme , Rein/métabolisme , Lipocaline-2/métabolisme , Souris , Souris de lignée C57BL , Souris knockout , ARN , Protéines de liaison à l'ARN/métabolisme , Lésion d'ischémie-reperfusion/métabolisme , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteursRÉSUMÉ
Increasing cases related to the pathogenicity of Enterovirus D68 (EV-D68) have made it a growing worldwide public health concern, especially due to increased severe respiratory illness and acute flaccid myelitis (AFM) in children. There are currently no vaccines or medicines to prevent or treat EV-D68 infections. Herein, we performed genome-wide transcriptional profiling of EV-D68-infected human rhabdomyosarcoma (RD) cells to investigate host-pathogen interplay. RNA sequencing and subsequent experiments revealed that EV-D68 infection induced a profound transcriptional dysregulation of host genes, causing significantly elevated inflammatory responses and altered antiviral immune responses. In particular, triggering receptor expressed on myeloid cells 1 (TREM-1) is involved in highly activated TREM-1 signaling processes, acting as an important mediator in EV-D68 infection, and it is related to upregulation of interleukin 8 (IL-8), IL-6, IL-12p70, IL-1ß, and tumor necrosis factor alpha (TNF-α). Further results demonstrated that NF-κB p65 was essential for EV-D68-induced TREM-1 upregulation. Moreover, inhibition of the TREM1 signaling pathway by the specific inhibitor LP17 dampened activation of the p38 mitogen-activated protein kinase (MAPK) signaling cascade, suggesting that TREM-1 mainly transmits activation signals to phosphorylate p38 MAPK. Interestingly, treatment with LP17 to inhibit TREM-1 inhibited viral replication and infection. These findings imply the pathogenic mechanisms of EV-D68 and provide critical insight into therapeutic intervention in enterovirus diseases.
Sujet(s)
Entérovirus humain D/pathogénicité , Infections à entérovirus/immunologie , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/immunologie , Lignée cellulaire , Cytokines/biosynthèse , Entérovirus humain D/immunologie , Infections à entérovirus/génétique , Analyse de profil d'expression de gènes , Humains , Médiateurs de l'inflammation/métabolisme , Système de signalisation des MAP kinases , Modèles immunologiques , RNA-Seq , Transduction du signal/immunologie , Facteur de transcription RelA/métabolisme , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteurs , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/génétique , Réplication virale/effets des médicaments et des substances chimiquesRÉSUMÉ
BACKGROUND/AIM: The aim of this study was to identify the association between SLAMF7 and TREM1 and anti-PD-1 drugs, and to determine whether they are molecular targets or predictors of responses to immunotherapy through induction of immunogenic cell death. MATERIALS AND METHODS: CRC cell lines over-expressing SLAMF7 and TREM1 were used to examine immunogenic and biological traits (e.g., proliferation and invasiveness) associated with factors related to anti-cancer immunity. In addition, multiplex immunofluorescence was used to examine immune cells in microsatellite instability-high (MSI-H) CRC and microsatellite stable (MSS) CRC. RESULTS: Proliferation rate and invasiveness of TREM1-over-expressing CRC cells were significantly greater than those of control cells (p<0.001 and 0.031, respectively), whereas SLAMF7-over-expressing CRC cells showed the opposite traits (p=0.005 and 0.002, respectively). SLAMF7-over-expressing DLD-1 cells harboring MSI-H showed increased apoptosis when treated with anti-PD-1 drugs, unlike SLAMF7-over-expressing SW480 cells harboring MSS. SLAMF7-over-expressing DLD1 and SW480 cells showed a marked increase in expression of the major cytokine mediator HMGB1 when exposed to anti-PD-1 drugs. Co-administration of anti-PD-1 drugs and TREM1 inhibitors induced apoptosis only in MSI-H HCT116 cells; HMGB1 was over-expressed regardless of microsatellite status. CONCLUSION: Expression of TREM1 and SLAMF7 is closely associated with immunogenic cell death, and TREM1 inhibitors may be an effective adjuvant that enhances anti-PD-1-mediated immunogenic cell death in MSS CRC.
Sujet(s)
Tumeurs colorectales/métabolisme , Cytotoxicité immunologique , Instabilité des microsatellites , Famille des molécules de signalisation de l'activation des lymphocytes/métabolisme , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/métabolisme , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Apoptose , Mouvement cellulaire , Prolifération cellulaire , Techniques de coculture , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/immunologie , Tumeurs colorectales/anatomopathologie , Régulation de l'expression des gènes tumoraux , Cellules HCT116 , Protéine HMGB1/génétique , Protéine HMGB1/métabolisme , Cellules HT29 , Humains , Inhibiteurs de points de contrôle immunitaires/pharmacologie , Invasion tumorale , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Récepteur-1 de mort cellulaire programmée/métabolisme , Transduction du signal , Famille des molécules de signalisation de l'activation des lymphocytes/génétique , Cellules THP-1 , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteurs , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/génétiqueRÉSUMÉ
Infection caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) in many cases is accompanied by the release of a large amount of proinflammatory cytokines in an event known as "cytokine storm", which is associated with severe coronavirus disease 2019 (COVID-19) cases and high mortality. The excessive production of proinflammatory cytokines is linked, inter alia, to the enhanced activity of receptors capable of recognizing the conservative regions of pathogens and cell debris, namely TLRs, TREM-1 and TNFR1. Here we report that peptides derived from innate immunity protein Tag7 inhibit activation of TREM-1 and TNFR1 receptors during acute inflammation. Peptides from the N-terminal fragment of Tag7 bind only to TREM-1, while peptides from the C-terminal fragment interact solely with TNFR1. Selected peptides are capable of inhibiting the production of proinflammatory cytokines both in peripheral blood mononuclear cells (PBMCs) from healthy donors and in vivo in the mouse model of acute lung injury (ALI) by diffuse alveolar damage (DAD). Treatment with peptides significantly decreases the infiltration of mononuclear cells to lungs in animals with DAD. Our findings suggest that Tag7-derived peptides might be beneficial in terms of the therapy or prevention of acute lung injury, e.g., for treating COVID-19 patients with severe pulmonary lesions.
Sujet(s)
Lésion pulmonaire aigüe/anatomopathologie , Cytokines/composition chimique , Peptides/métabolisme , Récepteur au facteur de nécrose tumorale de type I/métabolisme , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/métabolisme , Lésion pulmonaire aigüe/métabolisme , Animaux , Cytokines/génétique , Cytokines/métabolisme , Modèles animaux de maladie humaine , Humains , Interféron gamma/génétique , Interféron gamma/métabolisme , Agranulocytes/cytologie , Agranulocytes/effets des médicaments et des substances chimiques , Agranulocytes/métabolisme , Lipopolysaccharides/pharmacologie , Poumon/métabolisme , Poumon/anatomopathologie , Activation des lymphocytes/effets des médicaments et des substances chimiques , Mâle , Souris , Souris de lignée ICR , Peptides/composition chimique , Peptides/pharmacologie , Liaison aux protéines , Récepteur au facteur de nécrose tumorale de type I/antagonistes et inhibiteurs , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteursRÉSUMÉ
Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade. Using cells from patients and newly generated mouse models, we uncovered ELF4-mutant macrophages having hyperinflammatory responses to a range of innate stimuli. In mouse macrophages, Elf4 both sustained the expression of anti-inflammatory genes, such as Il1rn, and limited the upregulation of inflammation amplifiers, including S100A8, Lcn2, Trem1 and neutrophil chemoattractants. Blockade of Trem1 reversed inflammation and intestine pathology after in vivo lipopolysaccharide challenge in mice carrying patient-derived variants in Elf4. Thus, ELF4 restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory disorders such as IBD.
Sujet(s)
Protéines de liaison à l'ADN/génétique , Maladies auto-inflammatoires héréditaires/génétique , Maladies inflammatoires intestinales/génétique , Macrophages/immunologie , Facteurs de transcription/génétique , Animaux , Calgranuline A/métabolisme , Femelle , Régulation de l'expression des gènes/génétique , Maladies auto-inflammatoires héréditaires/immunologie , Maladies auto-inflammatoires héréditaires/anatomopathologie , Humains , Maladies inflammatoires intestinales/immunologie , Maladies inflammatoires intestinales/anatomopathologie , Antagoniste du récepteur à l'interleukine-1/immunologie , Lipocaline-2/métabolisme , Lipopolysaccharides/toxicité , Mâle , Souris , Souris de lignée C57BL , Souris knockout , Cellules Th17/immunologie , Transcription génétique/génétique , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteurs , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/métabolismeRÉSUMÉ
Chronic obstructive pulmonary disease (COPD) is a persistent respiratory disorder that is primarily caused by exposure to cigarette smoke (CS). Exosomes have emerged as crucial mediators of intercellular communication, but their role in CS-induced COPD is not fully understood. Here, we investigated whether exosomes derived from cigarette smoke extract (CSE)-treated mouse airway epithelial cells (MAECs) promote M1 macrophage polarization by upregulating triggering receptor expressed on myeloid cells-1 (TREM-1) expression during COPD pathogenesis. The exosomes isolated from PBS- or CSE-treated MAECs were named as ExoPBS or ExoCSE, respectively. Macrophages were transfected with si-TREM-1 to explore the role of TREM-1 in ExoCSE-induced M1 macrophage polarization. The lentivirus expressing shTREM-1 was injected into COPD model mice by intranasal instillation, which was carried out to explore the in vivo role of TREM-1 in ExoCSE-induced M1 macrophage polarization and CS-induced lung injury. We isolated ExoPBS and ExoCSE successfully, and found that ExoCSE promoted M1 macrophage polarization. Furthermore, we found that the promotion of ExoCSE to M1 macrophage polarization was partly reversed by TREM-1 knockdown. The results of animal experiments showed that ExoCSE administration aggravated CS-induced impairment in pulmonary function, lung injury and M1 macrophage polarization, which were partly rescued by TREM-1 silencing. Overall, ExoCSE promoted M1 macrophage polarization by upregulating TREM-1 expression, thereby aggravating the development of COPD.
Sujet(s)
Fumer des cigarettes/effets indésirables , Cellules épithéliales/anatomopathologie , Exosomes/métabolisme , Poumon/anatomopathologie , Activation des macrophages/immunologie , Broncho-pneumopathie chronique obstructive/anatomopathologie , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteurs , Animaux , Lignée cellulaire , Modèles animaux de maladie humaine , Cellules épithéliales/effets des médicaments et des substances chimiques , Cellules épithéliales/métabolisme , Poumon/effets des médicaments et des substances chimiques , Poumon/métabolisme , Mâle , Souris , Souris de lignée C57BL , Broncho-pneumopathie chronique obstructive/induit chimiquement , Broncho-pneumopathie chronique obstructive/immunologie , Broncho-pneumopathie chronique obstructive/métabolismeRÉSUMÉ
OBJECTIVE: The lipopolysaccharide- (LPS-) induced acute intestinal dysfunction model has been widely applied in recent years. Here, our aim was to investigate the effect of triggering receptor expressed on myeloid cells-1 (TREM1) inhibitor in LPS-induced acute intestinal dysfunction. METHODS: Male rats were randomly assigned into normal (saline injection), model (LPS and saline injection), and LP17 (LPS and LP17 (a synthetic TREM1 inhibitor) injection) groups. The levels of intestinal TREM1 expression were evaluated by immunohistochemistry and western blot. Intestinal permeability and apoptosis were separately assessed by the lactulose/mannitol (L/M) ratio and TUNEL assay. The levels of soluble TREM1 (sTREM1), TNF-α, IL-6, and IL-1ß were measured in the plasma and intestinal tissues by ELISA. The expression levels of NF-κB, high-mobility group box 1 (HMGB1), and toll-like receptor 4 (TLR-4) were measured with RT-qPCR and western blot. After transfection with si-TREM1 in LPS-induced intestinal epithelium-6 (IEC-6) cells, p-p65 and p-IκBα levels were detected by western blot. RESULTS: LP17-mediated TREM1 inhibition alleviated the intestine tissue damage in rats with LPS-induced acute intestinal dysfunction. LP17 attenuated the LPS-induced increase in sTREM1, TNF-α, IL-6, and IL-1ß levels in the plasma and intestinal tissues. Furthermore, intestine permeability and epithelial cell apoptosis were ameliorated by LP17. LP17 attenuated the LPS-induced increase in the expression of TREM1, HMGB1, TLR-4, and NF-κB in the intestine tissues. In vitro, TREM1 knockdown inactivated the NF-κB signaling in LPS-induced IEC-6 cells. CONCLUSION: LP17 could ameliorate LPS-induced acute intestinal dysfunction, which was associated with inhibition of intestinal apoptosis and inflammation response.
Sujet(s)
Apoptose , Inflammation/anatomopathologie , Intestins/anatomopathologie , Intestins/physiopathologie , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteurs , Maladie aigüe , Animaux , Inflammation/complications , Muqueuse intestinale/anatomopathologie , Muqueuse intestinale/physiopathologie , Lipopolysaccharides , Mâle , Facteur de transcription NF-kappa B/métabolisme , Perméabilité , Rat Sprague-Dawley , Transduction du signal , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/métabolismeRÉSUMÉ
Increasing evidence suggests that endoplasmic reticulum (ER) stress activates several pro-inflammatory signaling pathways in many diseases, including acute lung injury (ALI). We have reported that blocking triggering receptor expressed on myeloid cells 1 (TREM-1) protects against ALI by suppressing pulmonary inflammation in mice with ALI induced by lipopolysaccharides (LPS). However, the molecular mechanism underlying the TREM-1-induced pro-inflammatory microenvironment in macrophages remains unclearly. Herein, we aimed to determine whether TREM-1 regulates the inflammatory responses induced by LPS associated with ER stress activation. We found that the activation of TREM-1 by a monoclonal agonist antibody (anti-TREM-1) increased the mRNA and protein levels of IL-1ß, TNF-α, and IL-6 in primary macrophages. Treatment of the anti-TREM-1 antibody increased the expression of ER stress markers (ATF6, PERK, IRE-1α, and XBP-1s) in primary macrophages. While pretreatment with 4-PBA, an inhibitor of ER stress, significantly inhibited the expression of ER stress markers and pro-inflammatory cytokines and reduced LDH release. Furthermore, inhibiting the activity of the IRE-1α/XBP-1s pathway by STF-083010 significantly mitigated the increased levels of IL-1ß, TNF-α, and IL-6 in macrophages treated by the anti-TREM-1 antibody. XBP-1 silencing attenuated pro-inflammatory microenvironment evoked by activation of TREM-1. Besides, we found that blockade of TREM-1 with LR12 ameliorated ER stress induced by LPS in vitro and in vivo. In conclusion, we conclude that TREM-1 activation induces ER stress through the IRE-1α/XBP-1s pathway in macrophages, contributing to the pro-inflammatory microenvironment.
Sujet(s)
Stress du réticulum endoplasmique/physiologie , Macrophages/anatomopathologie , Protéines membranaires/métabolisme , Protein-Serine-Threonine Kinases/métabolisme , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/métabolisme , Protéine-1 liant la boite X/métabolisme , Lésion pulmonaire aigüe/anatomopathologie , Animaux , Anticorps monoclonaux/immunologie , Microenvironnement cellulaire/immunologie , Inflammation/immunologie , Interleukine-1 bêta/analyse , Interleukine-6/analyse , Lipopolysaccharides , Mâle , Souris , Souris de lignée C57BL , Pneumopathie infectieuse/induit chimiquement , Pneumopathie infectieuse/prévention et contrôle , Interférence par ARN , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteurs , Facteur de nécrose tumorale alpha/analyse , Protéine-1 liant la boite X/génétiqueRÉSUMÉ
Arginine synthesis deficiency due to the suppressed expression of ASS1 (argininosuccinate synthetase 1) represents one of the most frequently occurring metabolic defects of tumor cells. Arginine-deprivation therapy has gained increasing attention in recent years. One challenge of ADI-PEG20 (pegylated ADI) therapy is the development of drug resistance caused by restoration of ASS1 expression and other factors. The goal of this work is to identify novel factors conferring therapy resistance. Methods: Multiple, independently derived ADI-resistant clones including derivatives of breast (MDA-MB-231 and BT-549) and prostate (PC3, CWR22Rv1, and DU145) cancer cells were developed. RNA-seq and RT-PCR were used to identify genes upregulated in the resistant clones. Unbiased genome-wide CRISPR/Cas9 knockout screening was used to identify genes whose absence confers sensitivity to these cells. shRNA and CRISPR/Cas9 knockout as well as overexpression approaches were used to validate the functions of the resistant genes both in vitro and in xenograft models. The signal pathways were verified by western blotting and cytokine release. Results: Based on unbiased CRISPR/Cas9 knockout screening and RNA-seq analyses of independently derived ADI-resistant (ADIR) clones, aberrant activation of the TREM1/CCL2 axis in addition to ASS1 expression was consistently identified as the resistant factors. Unlike ADIR, MDA-MB-231 overexpressing ASS1 cells achieved only moderate ADI resistance both in vitro and in vivo, and overexpression of ASS1 alone does not activate the TREM1/CCL2 axis. These data suggested that upregulation of TREM1 is an independent factor in the development of strong resistance, which is accompanied by activation of the AKT/mTOR/STAT3/CCL2 pathway and contributes to cell survival and overcoming the tumor suppressive effects of ASS1 overexpression. Importantly, knockdown of TREM1 or CCL2 significantly sensitized ADIR toward ADI. Similar results were obtained in BT-549 breast cancer cell line as well as castration-resistant prostate cancer cells. The present study sheds light on the detailed mechanisms of resistance to arginine-deprivation therapy and uncovers novel targets to overcome resistance. Conclusion: We uncovered TREM1/CCL2 activation, in addition to restored ASS1 expression, as a key pathway involved in full ADI-resistance in breast and prostate cancer models.
Sujet(s)
Arginine/déficit , Hydrolases/pharmacologie , Polyéthylène glycols/pharmacologie , Animaux , Argininosuccinate synthase/déficit , Argininosuccinate synthase/génétique , Argininosuccinate synthase/métabolisme , Tumeurs du sein/génétique , Tumeurs du sein/métabolisme , Tumeurs du sein/thérapie , Systèmes CRISPR-Cas , Lignée cellulaire tumorale , Chimiokine CCL2/génétique , Chimiokine CCL2/métabolisme , Résistance aux médicaments antinéoplasiques/génétique , Femelle , Techniques de knock-out de gènes , Humains , Inflammation/génétique , Inflammation/métabolisme , Mâle , Souris , Souris de lignée BALB C , Souris nude , Modèles biologiques , Thérapie moléculaire ciblée , Médecine de précision , Tumeurs de la prostate/génétique , Tumeurs de la prostate/métabolisme , Tumeurs de la prostate/thérapie , Transduction du signal , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteurs , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/génétique , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/métabolisme , Régulation positive , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
Triggering receptor expressed on myeloid cells1 (TREM1) is a cellsurface protein expressed on tumorassociated macrophages (TAMs), the predominant inflammatory cells in the tumor microenvironment; however, the mechanisms for the influence of TREM1 on TAM polarization during liver cancer progression have not been investigated. In the present study, 20 patients diagnosed with hepatocellular carcinoma (HCC) who underwent surgery were enrolled, and TREM1 expression on M1/M2 macrophages and on M2 macrophages was assessed by immunohistochemical staining. Human leukemia monocytic cells (THP1) were differentiated into M2 macrophages using phorbol 12myristate 13acetate, IL4 and IL13. A specific short hairpin RNA was used to knockdown TREM1 expression. To investigate the effects of TREM1 downregulation in macrophages on the migration and invasion of liver cancer cells, HepG2 and MHCC97H cell lines were cocultured with specific conditioned media. Reverse transcriptionquantitative PCR and western blot analyses were used to detect M1 and M2 macrophage marker expression. The expression levels of proteins of the PI3K/AKT/mTOR signaling pathway were analyzed by western blotting, revealing that TREM1 expression in HCC tissues was significantly elevated compared with that in adjacent normal tissues, and TREM1 was highly expressed on the cell membranes of M2 macrophages in tumor tissues compared with in adjacent normal tissues. The present results demonstrated that TREM1 downregulation in macrophages shifted M2 macrophages towards an M1 phenotype, as defined by higher expression levels of M1associated markers and decreased expression levels of M2associated markers. In addition, TREM1 downregulation in macrophages suppressed migration and invasion of HepG2 and MHCC97H cells. Furthermore, TREM1knockdown in macrophages inhibited PI3K/AKT/mTOR activation in the polarization of M2 macrophages. In conclusion, downregulation of TREM1 expression in macrophages shifted M2 macrophages towards a M1 phenotype via inhibiting PI3K/AKT signaling. In addition, migration and invasion of HepG2 and MHCC97H cells were inhibited when this signaling pathway was blocked. The present findings suggest TREM1 as a novel potential therapeutic target for liver cancer management.
Sujet(s)
Carcinome hépatocellulaire/immunologie , Tumeurs du foie/immunologie , Macrophages/immunologie , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/métabolisme , Adulte , Sujet âgé , Antinéoplasiques/pharmacologie , Antinéoplasiques/usage thérapeutique , Biopsie , Carcinome hépatocellulaire/traitement médicamenteux , Carcinome hépatocellulaire/anatomopathologie , Carcinome hépatocellulaire/chirurgie , Lignée cellulaire tumorale , Régulation négative , Femelle , Techniques de knock-down de gènes , Hépatectomie , Humains , Foie/immunologie , Foie/anatomopathologie , Foie/chirurgie , Tumeurs du foie/traitement médicamenteux , Tumeurs du foie/anatomopathologie , Tumeurs du foie/chirurgie , Activation des macrophages/effets des médicaments et des substances chimiques , Macrophages/effets des médicaments et des substances chimiques , Macrophages/métabolisme , Mâle , Adulte d'âge moyen , Transduction du signal/effets des médicaments et des substances chimiques , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteurs , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/génétique , Microenvironnement tumoral/effets des médicaments et des substances chimiques , Microenvironnement tumoral/immunologieRÉSUMÉ
Iron withholding, an essential component of nutritional immunity, plays a fundamental role in host resistance to Salmonella infection. Our previous study showed that SpvB, an important pSLT-encoded cytotoxic effector, facilitated Salmonella pathogenesis within macrophages via perturbing cellular iron metabolism. However, the underlying mechanisms of SpvB in Salmonella-relevant disorders of systemic iron metabolism have not yet been identified. Here, we demonstrated that SpvB facilitated Salmonella to scavenge iron from the host by modulating the hepcidin-ferroportin axis, a key regulator of systemic iron metabolism. We observed that SpvB enhanced hepatic hepcidin synthesis in a STAT3-dependent manner, but not the BMP/SMAD pathway. This subsequently resulted in a reduction of the unique cellular iron exporter ferroportin, which facilitated hypoferremia and hepatic iron accumulation and ultimately countered the limitation of iron availability, thereby improving the chances of Salmonella survival and replication. Moreover, SpvB promoted the production of proinflammatory molecules associated with the infiltration of inflammatory cells via highly upregulating TREM-1 signaling. Our data supported a role of TREM-1 in SpvB-related dysregulation of host iron metabolism and suggested that targeting TREM-1 might provide a potential therapeutic strategy to prevent or alleviate Salmonella pathogenesis.
Sujet(s)
ADP ribose transferases/métabolisme , Transporteurs de cations/métabolisme , Hepcidines/métabolisme , Fer/métabolisme , Salmonelloses/métabolisme , Salmonella/pathogénicité , Facteurs de virulence/métabolisme , ADP ribose transferases/génétique , Animaux , Hépatocytes/métabolisme , Hepcidines/génétique , Humains , Inflammation , Foie/métabolisme , Foie/anatomopathologie , Macrophages/métabolisme , Souris , Facteur de transcription STAT-3/métabolisme , Salmonelloses/microbiologie , Transduction du signal , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteurs , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/métabolisme , Facteurs de virulence/génétiqueRÉSUMÉ
During sepsis, neutrophil activation induces endothelial cell (EC) dysfunction partly through neutrophil extracellular trap (NET) release. The triggering receptor expressed on myeloid cell-1 (TREM-1) is an orphan immune receptor that amplifies the inflammatory response mediated by Toll-like receptor-4 (TLR4) engagement. Although the key role of TLR4 signaling in NETosis is known, the role of TREM-1 in this process has not yet been investigated. Here, we report that TREM-1 potentiates NET release by human and murine neutrophils and is a component of the NET structure. In contrast, pharmacologic inhibition or genetic ablation of TREM-1 decreased NETosis in vitro and during experimental septic shock in vivo. Moreover, isolated NETs were able to activate ECs and impair vascular reactivity, and these deleterious effects were dampened by TREM-1 inhibition. TREM-1 may, therefore, constitute a new therapeutic target to prevent NETosis and associated endothelial dysfunction.
Sujet(s)
Endothélium vasculaire/immunologie , Pièges extracellulaires/physiologie , Granulocytes neutrophiles/immunologie , Sepsie/prévention et contrôle , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/physiologie , Adolescent , Adulte , Sujet âgé , Animaux , Endothélium vasculaire/métabolisme , Volontaires sains , Humains , Souris , Souris de lignée C57BL , Souris knockout , Adulte d'âge moyen , Sepsie/immunologie , Sepsie/anatomopathologie , Transduction du signal , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteurs , Jeune adulteRÉSUMÉ
Stroke ranks as the second leading cause of disability and death globally. Trigger receptors expressed on myeloid cells (TREM) -1 are responsible for the activation of the innate immune response and also play a critical role in inflammation. In this study, we reported the contribution of TREM-1 after ischemic damage in a rat middle cerebral artery occlusion (MCAO) model. This study also demonstrated that TREM-1 expression was upregulated following cerebral infarction in rats. TREM-1 inhibition was determined using its selective inhibitor, LP17, which indicated a neuroprotective effect on cerebral infarction damage. The findings revealed that inhibition of TREM-1 by administering LP17 improved cerebral damage and decreased ischemic areas and brain water contents. Moreover, LP17 decreased MCAO-induced microglial activation and neurodegeneration, evidenced by a reduction in the expression of microglial Iba-1 and FJ-B positive cells, and reversed neuronal loss. Besides, the contribution of LP17 to ischemic neuronal damage may be associated with a decrease in the production of pro-inflammatory cytokines, and enhanced production of anti-inflammatory cytokine IL-10. Both in vivo and in vitro studies showed that inhibiting TREM-1 attenuated ROS accumulation, lipid per-oxidation (LPO) contents such as malondialdehyde (MDA) and enhanced the superoxide dismutase (SOD) activity after ischemia. Inhibiting TREM-1 alleviated inflammation and pyroptosis found in MCAO rats. This was achieved through the inhibition of the levels of NLRP3, caspase-1, ASC (an apoptosis-associated speck-like protein containing a CARD) and gasdermin D. These results confirmed that inhibiting TREM-1 protects against ischemia-induced neuronal damage and alleviates microglial mediated neuro-inflammation by reducing oxidative stress and pyroptosis. Therefore, blocking TREM-1 expression provides an effective intervention for improving ischemic stroke.
Sujet(s)
Encéphalopathie ischémique/complications , Infarctus du territoire de l'artère cérébrale moyenne/complications , Maladies neurodégénératives/prévention et contrôle , Neuroprotecteurs/pharmacologie , Stress oxydatif/effets des médicaments et des substances chimiques , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteurs , Animaux , Lignée cellulaire , Infarctus cérébral/étiologie , Infarctus cérébral/métabolisme , Infarctus cérébral/prévention et contrôle , Cytokines/métabolisme , Malonaldéhyde/métabolisme , Souris , Microglie/métabolisme , Maladies neurodégénératives/étiologie , Maladies neurodégénératives/métabolisme , Pyroptose/effets des médicaments et des substances chimiques , Rat Sprague-Dawley , Espèces réactives de l'oxygène/métabolisme , Accident vasculaire cérébral/étiologie , Accident vasculaire cérébral/métabolisme , Accident vasculaire cérébral/prévention et contrôle , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/génétique , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/métabolismeRÉSUMÉ
BACKGROUND: Intestinal ischemia-reperfusion injury results in morbidity and mortality from both local injury and systemic inflammation and acute lung injury. Extracellular cold-inducible RNA-binding protein is a damage associated molecular pattern that fuels systemic inflammation and potentiates acute lung injury. We recently discovered a triggering receptor expressed on myeloid cells-1 serves as a novel receptor for extracellular cold-inducible RNA-binding protein. We developed a 7-aa peptide, named M3, derived from the cold-inducible RNA-binding protein, which interferes with cold-inducible RNA-binding protein's binding to a triggering receptor expressed on myeloid cells-1. Here, we hypothesized that M3 protects mice against intestinal ischemia-reperfusion injury. METHODS: Intestinal ischemia was induced in C57BL/6 mice via clamping of the superior mesenteric artery for 60 minutes. At reperfusion, mice were treated intraperitoneally with M3 (10 mg/kg body weight) or normal saline vehicle. Mice were killed 4 hours after reperfusion and blood and lungs were collected for various analysis. A 24-hours survival after intestinal ischemia-reperfusion was assessed. RESULTS: Serum levels of organ injury markers aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and lactate were increased with intestinal ischemia-reperfusion, while treatment with M3 significantly decreased their levels. Serum, intestinal, and lung levels of proinflammatory cytokines and chemokines were also increased by intestinal ischemia-reperfusion, and treatment with M3 significantly reduced these values. Intestinal ischemia-reperfusion caused significant histological intestinal and lung injuries, which were mitigated by M3. Treatment with M3 improved the survival from 40% to 80% after intestinal ischemia-reperfusion. CONCLUSION: Inhibition of triggering receptor expressed on myeloid cells-1 by an extracellular cold-inducible RNA-binding protein-derived small peptide (M3) decreased inflammation, reduced lung injury, and improved survival in intestinal ischemia-reperfusion injury. Thus, blocking the extracellular cold-inducible RNA-binding protein-triggering receptor expressed on myeloid cells-1 interaction is a promising therapeutic avenue for mitigating intestinal ischemia-reperfusion injury.
Sujet(s)
Intestins/vascularisation , Fragments peptidiques/usage thérapeutique , Protéines de liaison à l'ARN/usage thérapeutique , Lésion d'ischémie-reperfusion/prévention et contrôle , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteurs , Lésion pulmonaire aigüe/traitement médicamenteux , Lésion pulmonaire aigüe/immunologie , Animaux , Cytokines/métabolisme , Modèles animaux de maladie humaine , Évaluation préclinique de médicament , Humains , Mâle , Souris , Fragments peptidiques/immunologie , Fragments peptidiques/pharmacologie , Protéines de liaison à l'ARN/immunologie , Protéines de liaison à l'ARN/pharmacologie , Lésion d'ischémie-reperfusion/complications , Lésion d'ischémie-reperfusion/immunologie , Lésion d'ischémie-reperfusion/anatomopathologie , Transduction du signal/effets des médicaments et des substances chimiques , Transduction du signal/immunologie , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/métabolismeRÉSUMÉ
Groundbreaking studies in protein biophysics have identified the mechanisms of transmembrane signaling at the level of druggable protein-protein interactions (PPIs). This resulted in the development of the signaling chain homooligomerization (SCHOOL) strategy to modulate cell responses using receptor-specific peptides. Inspired by nature, these short peptides use ligand-independent mechanisms of receptor inhibition and demonstrate potent efficacy in vitro and in vivo. The SCHOOL strategy is especially important when receptor ligands are unknown. An example is the triggering receptor expressed on myeloid cells-1 (TREM-1) receptor, an emerging therapeutic target involved in the pathogenesis of most inflammatory diseases. Here, I discuss advances in the field with a focus on TREM-1 inhibitory SCHOOL peptides that offer new hope for a 'magic bullet' cure for cancer, arthritis, sepsis, retinopathy, and other medical challenges.
Sujet(s)
Facteurs immunologiques/usage thérapeutique , Peptides/usage thérapeutique , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteurs , Animaux , Arthrite/traitement médicamenteux , Humains , Ligands , Tumeurs/traitement médicamenteux , Rétinopathies/traitement médicamenteux , Sepsie/traitement médicamenteuxRÉSUMÉ
BACKGROUND: Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern, which is released into the circulation after hemorrhagic shock (HS). Recently, we discovered that triggering receptor expressed on myeloid cells-1 (TREM-1) serves as a new receptor of eCIRP to exaggerate inflammation. Here, we hypothesize that by inhibiting the interaction between eCIRP and TREM-1 with the use of a novel short peptide derived from human eCIRP known as M3, we can inhibit the inflammatory response and acute lung injury in HS. METHODS: Hemorrhagic shock was induced using C57BL/6 mice by cannulating both femoral arteries. One femoral artery was used for removal of blood while the other was used for continuous monitoring of mean arterial blood pressure. The mean arterial pressure of 25 mm Hg to 30 mm Hg was maintained for 90 minutes, followed by a resuscitation phase of 30 minutes with 1 mL of normal saline. The treatment group was given 10 mg/kg of M3 during the resuscitation phase. Four hours after resuscitation, serum and lungs were collected and analyzed for various injury and inflammatory markers by using colorimetry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. RESULTS: There was an increase in the serum levels of tissue injury markers (alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase) as well as cytokines (TNF-α and IL-6) when comparing the vehicle group versus the sham group. This increase was significantly inhibited in the M3-treated group. The mRNA expression of proinflammatory cytokines TNF-α, IL-6, and IL-1ß and the chemokines MIP-2 and KC in lungs was significantly increased in the vehicle-treated HS mice, while their expression was significantly decreased in M3-treated HS mice. Finally, M3 treatment significantly decreased the lung injury score compared with vehicle-treated HS mice. CONCLUSION: The novel eCIRP-derived TREM-1 antagonist (M3) can be a potential therapeutic adjunct in the management of hemorrhagic shock.
Sujet(s)
Lésion pulmonaire aigüe/prévention et contrôle , Fragments peptidiques/pharmacologie , Choc hémorragique/traitement médicamenteux , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/antagonistes et inhibiteurs , Lésion pulmonaire aigüe/sang , Lésion pulmonaire aigüe/immunologie , Lésion pulmonaire aigüe/anatomopathologie , Alarmines/composition chimique , Alarmines/immunologie , Animaux , Modèles animaux de maladie humaine , Humains , Médiateurs de l'inflammation/sang , Poumon/effets des médicaments et des substances chimiques , Poumon/immunologie , Poumon/anatomopathologie , Mâle , Souris , Fragments peptidiques/composition chimique , Fragments peptidiques/immunologie , Fragments peptidiques/usage thérapeutique , Protéines de liaison à l'ARN/composition chimique , Protéines de liaison à l'ARN/immunologie , Choc hémorragique/sang , Choc hémorragique/complications , Choc hémorragique/immunologie , Récepteur de déclenchement de type-1 exprimé sur les cellules myéloïdes/immunologieRÉSUMÉ
Neuroinflammation is initiated in response to ischemic stroke, generally with the hallmarks of microglial activation and collateral brain injury contributed by robust inflammatory effects. Triggering receptor expressed on myeloid cells (TREM)-1, an amplifier of the innate immune response, is a critical regulator of inflammation. This study identified that microglial TREM-1 expression was upregulated following cerebral ischemic injury. After pharmacologic inhibition of TREM-1 with synthetic peptide LP17, ischemia-induced infarction and neuronal injury were substantially alleviated. Moreover, blockade of TREM-1 can potentiate cellular proliferation and synaptic plasticity in hippocampus, resulting in long-term functional improvement. Microglial M1 polarization and neutrophil recruitment were remarkably abrogated as mRNA levels of M1 markers, chemokines, and protein levels of myeloperoxidase and intracellular adhesion molecule-1 (ICAM-1) were decreased by LP17. Mechanistically, both in vivo and in vitro, we delineated that TREM-1 can activate downstream pro-inflammatory pathways, CARD9/NF-κB, and NLRP3/caspase-1, through interacting with spleen tyrosine kinase (SYK). In addition, TREM-1-induced SYK initiation was responsible for microglial pyroptosis by elevating levels of gasdermin D (GSDMD), N-terminal fragment of GSDMD (GSDMD-N), and forming GSDMD pores, which can facilitate the release of intracellular inflammatory factors, in microglia. In summary, microglial TREM-1 receptor yielded post-stroke neuroinflammatory damage via associating with SYK.