Activation of toll-like receptor 4/nuclear factor-kappa B signaling by triggering a receptor expressed on myeloid cells 1 promotes alveolar macrophage M1 polarization and exacerbates septic acute lung injury.

BACKGROUND: Septic acute lung injury (ALI) is a life-threatening condition commonly occurring in the intensive care unit. Inflammation is considered as the basic pathological response of septic ALI. Triggering receptor expressed on myeloid cells 1 (TREM1) is a member of the immunoglobulin superfamily receptors that regulates the inflammatory response. However, the role of TREM1 in septic ALI has not yet been reported. METHODS: Cell viability was tested using the MTT assay. TdT-mediated dUTP nick end labeling assay and flow cytometry were used for apoptosis. The level of protein was detected using western blot analysis. The levels of tumor necrosis factor-α and interleukin-1ß were assessed using enzyme-linked immunosorbent assay. The lactate dehydrogenase content was assessed using the assay kit. Myeloperoxidase activity was determined using an assay. Histology of lung tissue was further analyzed through hematoxylin-eosin staining. RESULTS: We found that TREM1 knockdown by transfection with si-TREM1 inhibited lipopolysaccharide (LPS)-induced cell apoptosis of alveolar macrophage cell line MH-S. The LPS stimulation caused M1 polarization of MH-S cells, which could be reversed by TREM1 knockdown. In vivo assays proved that si-TREM1 injection improved lung injury and inflammation of cecal ligation and puncture-induced ALI in mice. In addition, TREM1 knockdown suppressed the activation of toll-like receptor 4/nuclear factor-kappa B signaling, implying the involvement of TLR4 in the effects of TREM1 in response to LPS stimulation. CONCLUSIONS: This study examined the proinflammatory role of TREM1 in septic ALI and its regulatory effect on alveolar macrophage polarization. These results suggest that TREM1 could potentially serve as a therapeutic target in the prevention and treatment of ALI.

Systemic neutrophils are triggered by respiratory Bacillus Calmette- Guérin and mediate pulmonary mycobacterial clearance in synergy with the triggering receptor expressed on myeloid cells 1.

Tuberculosis remains a threat to public health. The only approved vaccine, Bacillus Calmette-Guérin (BCG), is administered intradermally and provides limited protection, and its effect on innate immunity via the respiratory route has not been fully elucidated. A mouse model with genetically depleted TREM1 and seven-color flow cytometry staining were used to characterize the comprehensive immune response induced by respiratory BCG, through evaluating organ bacterial loads, lung histopathology, and lung immunohistochemistry. During respiratory BCG infection, the murine lungs displayed effective bacterial clearance. Notably, marked differences in neutrophils were observed between thymus and bone marrow cells, characterized by a significant increase in the expression of the triggering receptor expressed on myeloid cells 1 (TREM1). Subsequently, upon depletion of TREM1, a reduction in pulmonary neutrophils was observed, which further exacerbated bacterial loads and resulted in worsened pathology following respiratory BCG infection. In summary, up-regulated expression of TREM1 in rapidly increasing circulating neutrophil by pulmonary BCG is required for an efficient host response to BCG infection, and suggests the important role of TREM1 in neutrophil-related pulmonary bacteria clearance and pathology.

Circulating sTREM-1 as a predictive biomarker of pediatric multisystemic inflammatory syndrome (MIS-C).

The exacerbation of the inflammatory response caused by SARS-CoV-2 in adults promotes the production of soluble mediators that could act as diagnostic and prognostic biomarkers for COVID-19. Among the potential biomarkers, the soluble triggering receptor expressed on myeloid cell-1 (sTREM-1) has been described as a predictor of inflammation severity. The aim was to evaluate sTREM-1 and cytokine serum concentrations in pediatric patients during the acute and convalescent phases of COVID-19. This was a prospective study that included 53 children/adolescents with acute COVID-19 (Acute-CoV group); 54 who recovered from COVID-19 (Post-CoV group) and 54 controls (Control group). Preexisting chronic conditions were present in the three groups, which were defined as follows: immunological diseases, neurological disorders, and renal and hepatic failures. The three groups were matched by age, sex, and similar preexisting chronic conditions. No differences in sTREM-1 levels were detected among the groups or when the groups were separately analyzed by preexisting chronic conditions. However, sTREM-1 analysis in the seven multisystemic inflammatory syndrome children (MIS-C) within the Acute-Cov group showed that sTREM-1 concentrations were higher in MIS-C vs non-MIS-C acute patients. Then, the receiver operating curve analysis (ROC) performed with MIS-C acute patients revealed a significant AUC of 0.870, and the sTREM-1 cutoff value of > 5781 pg/mL yielded a sensitivity of 71.4 % and a specificity of 91.3 % for disease severity, and patients with sTREM-1 levels above this cutoff presented an elevated risk for MIS-C development in 22.85-fold (OR = 22.85 [95 % CI 1.64-317.5], p = 0.02). The cytokine analyses in the acute phase revealed that IL-6, IL-8, and IL-10 concentrations were elevated regardless of whether the patient developed MIS-C, and those levels decreased in the convalescent phase, even when compared with controls. Spearman correlation analysis generated positive indexes between sTREM-1 and IL-12 and TNF-α concentrations, only within the Acute-CoV group. Our findings revealed that sTREM-1 in pediatric patients has good predictive accuracy as an early screening tool for surveillance of MIS-C cases, even in patients with chronic underlying conditions.

The Effect of Soluble TREM-1 in Idiopathic Granulomatous Mastitis.

BACKGROUND AND OBJECTIVES: The aim of this study is to investigate the effect of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in idiopathic granulomatous mastitis (IGM). METHODS: This case-control study was conducted in Saglik Bilimleri and Necmettin Erbakan Universities. Sixty patients with IGM diagnosis (Group P) and 25 healthy females as control group (Group C) were included. Group P was divided into two subgroups according to the activity of disease: patients with active lesion (Group PA), and patients without any symptoms, in remission (Group PR). The ELISA method was used to measure sTREM-1 level. RESULTS: Group P's sTREM-1 were higher than Group C (p < .0001). The difference between sTREM-1 levels of Groups PA, PR and C was significant statistically (p < .0001). Group PA's sTREM-1 levels were higher than Group C (p < .0001). Also, sTREM-1 levels of Group PR were higher than Group C (p = .006). When sTREM-1 levels of patients receiving steroid therapy and did not in Group PR were analyzed, the sTREM-1 levels of the patients not receiving steroid treatment were found to be statistically higher than Group C (p = .002). Although the sTREM-1 levels of the patients who did not receive steroid therapy were higher than those who received steroid therapy, the difference was not statistically significant (p > .05). CONCLUSION: We concluded that the detected high sTREM-1 levels contributed to inflammation in IGM. In particular, blockade of TREM may be a promising treatment option in resistant or multiple recurrent patients.

The relationship between vitamin D receptor gene and TREM-1 gene polymorphisms and the susceptibility and prognosis of neonatal sepsis.

OBJECTIVE: The objective of this was to study the relationship between vitamin D receptor (VDR) and triggering receptor expressed on myeloid cells 1 (TREM-1) gene single-nucleotide polymorphisms (SNP) and neonatal sepsis susceptibility and prognosis. METHODS: The blood of 150 neonatal sepsis patients and 150 normal neonates was collected, and genomic DNA was extracted. Sanger sequencing was used to analyze the genotypes of VDR rs739837 and TREM-1 rs2234246. RESULTS: Vitamin D receptor rs739837 locus GT, TT genotype, dominant model, and recessive model were all protective factors for sepsis (0 < OR < 1, p < 0.05). The risk of sepsis in carriers of the rs739837 G allele was 0.65 times that of the rs739837 T allele (95% CI: 0.50-0.83, p < 0.001), CT, TT, dominant model, and recessive model at rs2234246 were risk factors for sepsis (OR > 1, p < 0.05). The risk of sepsis in carriers of the rs739837 T allele was 1.38 times that of carriers of the C allele (95% CI: 1.16-1.61, p < 0.001). The polymorphisms of VDR gene rs739837 and TREM-1 gene rs2234246 were not significantly correlated with the survival of patients with neonatal sepsis (p > 0.05). CONCLUSION: Vitamin D receptor gene rs739837 locus G>T is associated with a reduction in the risk of neonatal sepsis, TREM-1 rs2234246 C>T is associated with the increased risk of neonatal sepsis, but none of them was significantly associated with the prognosis of neonatal sepsis.

Soluble TREM-1, as a new ligand for the membrane receptor Robo2, promotes hepatic stellate cells activation and liver fibrosis.

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.

TREM (Triggering Receptor Expressed on Myeloid Cells)-1 Inhibition Attenuates Neuroinflammation via PKC (Protein Kinase C) δ/CARD9 (Caspase Recruitment Domain Family Member 9) Signaling Pathway After Intracerebral Hemorrhage in Mice.

Background and Purpose: Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with high mortality and disability. Inflammatory response promotes secondary brain injury after ICH. TREM (triggering receptor expressed on myeloid cells)-1 is a key regulator of inflammation. The aim of this study was to evaluate the role of TREM-1 in neuroinflammatory response after ICH in mice. Methods: CD1 mice (n=275) were used in this study. Mice were subjected to ICH by autologous blood injection. TREM-1 knockout CRISPR was administered intracerebroventricularly to evaluate the role of TREM-1 after ICH. A selective TREM-1 inhibitor, LP17, was administered intranasally 2 hours after ICH. To elucidate TREM-1 signaling pathway, CARD9 (caspase recruitment domain family member 9) activation CRISPR was administered with LP17 and TREM-1 activating anti-mouse TREM-1 monoclonal antibody (mAb) was administered with Rottlerin, a specific PKC (protein kinase C) δ inhibitor. Lastly, to evaluate the role of HMGB1 (high-mobility group box 1) in TREM-1 mediated microglia activation, glycyrrhizin, an inhibitor of HMBG1 was administered with TREM-1 activating mAb. Neurobehavioral test, brain water content, Western blot, immunofluorescence staining, and coimmunoprecipitation was performed. Results: TREM-1 knockout reduced ICH-induced neurobehavioral deficits and neuroinflammatory response. The temporal expression of HMGB1, TREM-1, PKC δ, and CARD9 increased after ICH. TREM-1 was expressed on microglia. Intranasal administration of LP17 significantly decreased brain edema and improved neurobehavioral outcomes at 24 and 72 hours after ICH. LP17 promoted M2 microglia polarization and reduced proinflammatory cytokines after ICH, which was reversed with CARD9 activation CRISPR. TREM-1 mAb increased neurobehavior deficits, proinflammatory cytokines, and reduced M2 microglia after ICH, which was reversed with Rottlerin. HMBG1 interaction with TREM-1 increased after ICH, and glycyrrhizin reduced neuroinflammation and promoted M2 microglia which was reversed with TREM-1 mAb. Conclusions: This study demonstrated that TREM-1 enhanced neuroinflammation by modulating microglia polarization after ICH, and this regulation was partly mediated via PKC δ/CARD9 signaling pathway and increased HMGB1 activation of TREM-1.

TREM-1 aggravates chronic obstructive pulmonary disease development via activation NLRP3 inflammasome-mediated pyroptosis.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a major cause of death globally. Inflammation plays a crucial role in COPD development. Pyroptosis, an inflammatory form of cell death, may involve in the pathogenesis of COPD. This study aims to explore the role and action mechanism of triggering receptor expressed on myeloid cells 1 (TREM-1) in COPD. METHODS: Here, cigarette smoke stimulation was used to establish COPD model in mice. Cigarette smoke extract combined with lipopolysaccharide was used to stimulate RAW264.7 cells for COPD model in vitro. QRT-PCR and Western blot were performed to detect the expression of mRNA and proteins, respectively, in the lung tissues and cells. Concentration of cytokines was measured using ELISA. H&E staining was used to analyze the pathological changes in lung tissues. The number of infiltrated macrophage was examined using immunofluorescence. LP17 was used to silence the expression of TREM-1. RESULTS: The results showed that TREM-1 was highly expressed in COPD. In vivo, inhibition of TREM-1 effectively improved the injury in lung tissues of COPD mouse, and reduced the infiltration of macrophages. Moreover, inhibition of TREM-1 in vivo and in vitro notably suppressed the activation of NLRP3 inflammasome and pyroptosis. Rescue experiment demonstrated that TREM-1 activated pyroptosis via regulating NLRP3 inflammasome. CONCLUSION: Overall, our results proved that TREM-1 promoted the lung injury and inflammation in COPD mouse through activation of NLRP3 inflammasome-mediated pyroptosis. Our data indicated a novel mechanism of TREM-1 in COPD development, and maybe provide a novel therapeutic target for COPD treatment.

Diagnostic value of serum soluble triggering expressed receptor on myeloid cells 1 (sTREM-1) in suspected sepsis: a meta-analysis.

BACKGROUND: We aim to synthesize the up-to-date studies to investigate the diagnostic value of serum soluble triggering expressed receptor on myeloid cells 1 (sTREM-1) in suspected sepsis. RESULTS: A total of 19 studies with 2418 patients were finally enrolled in the meta-analysis. The pooled sensitivity was 0.82 (95% CI 0.73 to 0.89), specificity 0.81 (95% CI 0.75 to 0.86), positive likelihood ratio 4.3 (95% CI 3.02 to 6.12), negative likelihood ratio 0.22 (95% CI 0.24 to 0.35), diagnostic odds ratio 20 (95% CI 9 to 41) and AuROC 0.88 (95% CI 0.85 to 0.91). The meta-regression analysis revealed that the sample size, reference standard description, prevalence of sepsis in the trials and consecution of patient recruitment might be the source of heterogeneity. CONCLUSIONS: The serum sTREM-1 had a moderate ability in diagnosis in suspected sepsis based on the current studies. However, more large-scale studies were needed to further evaluate the diagnostic accuracy of sTREM-1.

Impact of soymilk consumption on 2,4-dinitrofluorobenzene-induced contact hypersensitivity and gut microbiota in mice.

Soymilk is rich in phytochemicals such as soy isoflavones (SIs) and soyasaponins (SSs). Dietary SIs and SSs display inhibitory effects on contact hypersensitivity (CHS), which was reported in a mouse model for allergic contact dermatitis (ACD); however, the beneficial effects of soymilk consumption on CHS remain unknown. Here, we studied the effects of drinking soymilk on CHS and gut microbiota. Soymilk consumption attenuated ear oedema and swelling, decreased the infiltration of Gr-1-positive cells into ear tissues, and reduced the production of chemokine (C-X-C motif) ligand 2 and triggering receptor expressed on myeloid cells-1 in ear tissues. The analysis of bacterial 16S ribosomal RNA gene sequences indicated that CHS caused changes in the gut microbiota structure and that consuming soymilk reduced these changes. These results suggest that soymilk consumption may be of therapeutic value for patients with ACD and may help control the balance of intestinal microbiota.

Protective effects of guggulsterone against colitis are associated with the suppression of TREM-1 and modulation of macrophages.

Triggering receptor expressed on myeloid cells 1 (TREM-1)-expressing intestinal macrophages are significantly increased in the colons of patients with inflammatory bowel disease (IBD). We focused here on the effects of guggulsterone on macrophage modulation in colitis as a potential therapeutic molecule in human IBD and explore the underlying mechanisms. Gene expression in macrophages was examined and wound-healing assay using HT-29 cells was performed. Colitis in wild-type and IL-10-, Toll-like receptor 4 (TLR4)-, and myeloid differentiation primary response 88 (MyD88)-deficient mice was induced via the administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the colon. In both in vitro and in vivo experiments, guggulsterone suppressed intestinal inflammation amplified by TREM-1 stimulation, in which the suppression of NF-κB, activating protein-1, and proteasome pathways was involved. In the TNBS-induced colitis model, guggulsterone reduced disease activity index scores and TREM-1 expression, stimulated IL-10 production, and improved survival in wild-type mice. These effects were not observed in IL-10-, TLR4-, and MyD88-deficient mice. Guggulsterone also suppressed M1 polarization, yet induced the M2 phenotype in macrophages from IBD patients as well as from mice. These findings indicate that guggulsterone blocks the hyperactivation of macrophages via TREM-1 suppression and induces M2 polarization via IL-10 mediated by the TLR4 signaling pathway. Furthermore, this study provides a new rationale for the therapeutic potential of guggulsterone in the treatment of IBD. NEW & NOTEWORTHY We found that guggulsterone attenuates triggering receptor expressed on myeloid cells 1 (TREM-1)-mediated hyperactivation of macrophages and polarizes macrophages toward the M2 phenotype. This was mediated by IL-10 and partly Toll-like receptor 4 signaling pathways. Overall, these data support that guggulsterone as a natural plant sterol modulates macrophage phenotypes in colitis, which may be of novel therapeutic importance in inflammatory bowel disease treatment.

Blockade of TREM-1 prevents vitreoretinal neovascularization in mice with oxygen-induced retinopathy.

In pathological retinal neovascularization (RNV) disorders, the retina is infiltrated by activated leukocytes and macrophages. Triggering receptor expressed on myeloid cells 1 (TREM-1), an inflammation amplifier, activates monocytes and macrophages and plays an important role in cancer, autoimmune and other inflammation-associated disorders. Hypoxia-inducible TREM-1 is involved in cancer angiogenesis but its role in RNV remains unclear. Here, to close this gap, we evaluated the role of TREM-1 in RNV using a mouse model of oxygen-induced retinopathy (OIR). We found that hypoxia induced overexpression of TREM-1 in the OIR retinas compared to that of the room air group. TREM-1 was observed specifically in areas of pathological RNV, largely colocalizing with macrophage colony-stimulating factor (M-CSF) and CD45- and Iba-1-positive cells. TREM-1 blockade using systemically administered first-in-class ligand-independent TREM-1 inhibitory peptides rationally designed using the signaling chain homooligomerization (SCHOOL) strategy significantly (up to 95%) reduced vitreoretinal neovascularization. The peptides were well-tolerated when formulated into lipopeptide complexes for peptide half-life extension and targeted delivery. TREM-1 inhibition substantially downregulated retinal protein levels of TREM-1 and M-CSF suggesting that TREM-1-dependent suppression of pathological angiogenesis involves M-CSF. Targeting TREM-1 using TREM-1-specific SCHOOL peptide inhibitors represents a novel strategy to treat retinal diseases that are accompanied by neovascularization including retinopathy of prematurity.

The triggering receptor expressed by myeloid cells-1 activates TLR4-MyD88-NF-κB-dependent signaling to aggravate ventilation-induced lung inflammation and injury in mice.

The triggering receptor expressed by myeloid cells-1 (TREM-1) plays an important role in infectious and autoimmune diseases but how it contributes to ventilation-induced lung injury (VILI) and inflammation is unclear. Here, we examine the possibility that TREM-1 activates signaling dependent on Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88) and nuclear factor (NF)-κB, which leads in turn to VILI. In a mouse model of VILI, which we validated based on lung edema and histopathology as well as cytokine levels, we examine mRNA and protein levels of TREM-1, TLR4, MyD88, NF-κB and its inhibitory protein I-κB in animals subjected to ventilation at normal or high tidal volume. The extent of lung edema, injury and inflammation were higher in the high tidal volume animals, as were the expression levels of all proteins examined. Treatment with TREM-1 agonist aggravated these effects, whereas treatment with TREM-1 antagonist attenuated them. Our results suggest that aggravation of VILI by TREM-1 in mice may be associated with TLR4-MyD88-NF-κB-dependent signaling.

Assessment of Serum sTREM-1 as a Marker of Subclinical Inflammation in Diarrhea-Predominant Patients with Irritable Bowel Syndrome.

BACKGROUND: Irritable bowel disease (IBS) is viewed upon as a functional disorder of subclinical inflammatory changes in recent years, and there is no reliable biomarker. Triggering receptor expressed on myeloid cells 1 (TREM-1), also produced in a soluble form (sTREM-1), is involved in the activation of inflammatory cascades of intracellular events and may play a role in pathogenesis of IBS. AIM: To investigate whether serum sTREM-1 level can be used as a marker of subclinical inflammation in D-IBS. METHODS: Abdominal pain was quantified by a validated questionnaire. Expression level of TREM-1 in colonic mucosa as well as sTREM-1 level in serum was also detected. Furthermore, we investigated the involvement of TREM-1-associated macrophage activation in IBS-like visceral hypersensitivity. RESULTS: No evidence for obvious inflammation was found in D-IBS patients. Serum sTREM-1 level in D-IBS patients was significantly higher than that in HCs, which was also significantly correlated with abdominal pain scores. We showed a marked increase in the proportion of TREM-1-expressing macrophages in D-IBS, which was significantly correlated with abdominal pain scores. Functionally, gadolinium chloride (GdCl3), a macrophage selective inhibitor, or LP17, the TREM-1-specific peptide, significantly suppressed the visceral hypersensitivity in trinitrobenzene sulfonic acid (TNBS)-treated mice with IBS-like visceral hypersensitivity. CONCLUSIONS: Serum sTREM-1 level is significantly higher in D-IBS patients and positively correlates with abdominal pain, which may be initiated by TREM-1-associated macrophage activation, indicating the existence of subclinical inflammation in D-IBS. Therefore, serum sTREM-1 is a potential marker of subclinical inflammation in D-IBS.

Rationally designed ligand-independent peptide inhibitors of TREM-1 ameliorate collagen-induced arthritis.

Triggering receptor expressed on myeloid cells 1 (TREM-1) is critically involved in the pathogenesis of rheumatoid arthritis (RA). In contrast to cytokine blockers, therapeutic blockade of TREM-1 can blunt excessive inflammation while preserving the capacity for microbial control. However, the nature of the TREM-1 ligand(s) and mechanisms of TREM-1 signalling are still not yet well understood, impeding the development of clinically relevant inhibitors of TREM-1. The aim of this study was to evaluate the anti-arthritic activity of a novel, ligand-independent TREM-1 inhibitory nonapeptide GF9 that was rationally designed using the signalling chain homo oligomerization (SCHOOL) model of cell signalling. Free GF9 and GF9 bound to macrophage-targeted nanoparticles that mimic human high-density lipoproteins (GF9-HDL) were used to treat collagen-induced arthritis (CIA). We also tested if 31-mer peptides with sequences from GF9 and helices 4 (GE31) and 6 (GA31) of the major HDL protein, apolipoprotein A-I, are able to perform three functions: assist in the self-assembly of GA/E31-HDL, target these particles to macrophages and block TREM-1 signalling. We showed that GF9, but not control peptide, ameliorated CIA and protected against bone and cartilage damage. The therapeutic effect of GF9 was accompanied by a reduction in the plasma levels of macrophage colony-stimulating factor and pro-inflammatory cytokines such as tumour necrosis factor-α, interleukin (IL)-1 and IL-6. Incorporation of GF9 alone or as a part of GE31 and GA31 peptides into HDL significantly increased its therapeutic efficacy. Collectively, our findings suggest that TREM-1 inhibitory SCHOOL sequences may be promising alternatives for the treatment of RA.

Triggering receptor expressed on myeloid cells-1 (TREM-1) deficiency augments BAFF production to promote lupus progression.

Sensing of nucleic acids by pattern recognition receptors is the key for the initiation and development of systemic lupus erythematosus (SLE). Triggering receptor expressed on myeloid cells-1 (TREM-1) is a novel innate immune receptor, which can amplify Toll-like receptor (TLR)-induced inflammatory responses. Although patients with lupus exhibit increased serum levels of soluble TREM-1 (sTREM-1), the role of TREM-1 in SLE remains unknown. In current study, we found serum sTREM-1 levels were significantly increased in lupus patients and positively correlated with disease activity. Additionally, diseased B6.lpr mice had elevated TREM-1 in the serum, spleen, and lymph nodes. To investigate the role of TREM-1 in lupus, we established Trem-1-/-.lpr mice. Trem-1-/-.lpr mice exhibited lower survival rates and more severe lupus symptoms, including elevated proteinuria, serum anti-dsDNA antibody levels, renal immune complex depositions and lymphocyte subpopulation expansions in both the spleen and lymph nodes. Besides, Trem-1-/-.lpr mice expressed higher serum B cell-activating factor (BAFF) levels and lymph node dendritic cells (DCs) were the major source of increased BAFF. Activation of membrane-bound TREM-1 could suppress TLR9-induced BAFF expression in bone marrow-derived DCs of B6.lpr mice. Moreover, levels of sTREM-1, which could act as an antagonist of membrane-bound TREM-1, were positively correlated with levels of BAFF in the sera of lupus patients. Our findings suggest a novel modulatory role of TREM-1 in the pathogenesis of SLE. sTREM-1 production is a useful diagnostic marker and a molecular target for combination therapy of lupus.

Inhibitory effects of dietary soyasaponin on 2,4-dinitrofluorobenzene-induced contact hypersensitivity in mice.

Soyasaponins (SSs) abundant in soybean have anti-inflammatory activities; however, their therapeutic effects on allergic contact dermatitis (ACD) remain unknown. To assess the effects of SS-enriched diets on ACD, we used a mouse model of contact hypersensitivity (CHS). Mice were fed low-dose or high-dose SS-containing diets for 3 weeks prior to CHS induction with 2,4-dinitrofluorobenzene (DNFB). The low-dose SS diet attenuated DNFB-induced ear swelling and tissue oedema, and reduced the number of infiltrating Gr-1-positive myeloid cells. Low-dose, but not high-dose, SSs decreased chemokine (C-X-C motif) ligand 2 (CXCL2) and triggering receptor expressed on myeloid cells (TREM)-1 production in ear tissues, compared to a control. Taxonomic 16S rRNA analysis revealed significant alterations in faecal microbiota caused by CHS, which were reversed by low-dose SSs. The low-dose SS and non-CHS groups clustered together, while the high-dose SS group split between CHS and non-CHS clusters. Our results demonstrated that low-dose SSs alleviated CHS symptoms by attenuating inflammation and improving the intestinal microbiota composition, suggesting that dietary SSs may have beneficial effects on ACD.

Novel TREM-1 Inhibitors Attenuate Tumor Growth and Prolong Survival in Experimental Pancreatic Cancer.

Pancreatic cancer (PC) is a highly lethal cancer with an urgent need to expand the limited treatment options for patients. Tumor-associated macrophages (TAMs) promote tumor aggressiveness and metastasis. High expression of triggering receptor expressed on myeloid cells 1 (TREM-1) on TAMs directly correlates with poor survival in patients with non-small cell lung cancer (NSCLC). We have previously hypothesized that blockade of TREM-1 could be a promising therapeutic strategy to treat cancer and shown that the novel, ligand-independent TREM-1 inhibitory peptides rationally designed using the signaling chain homooligomerization (SCHOOL) strategy suppress NSCLC growth in vivo. Here, we evaluated the therapeutic potential of these inhibitors in three human PC xenograft mouse models. Administration of SCHOOL peptides resulted in a strong antitumor effect achieving an optimal treatment/control (T/C) value of 19% depending on the xenograft and formulation used and persisting even after treatment was halted. The effect correlated significantly with increased survival and suppressed TAM infiltration. The peptides were well-tolerated when deployed either in free form or formulated into lipopeptide complexes for peptide half-life extension and targeted delivery. Finally, blockade of TREM-1 significantly reduced serum levels of interleukin (IL)-1α, IL-6, and macrophage colony-stimulating factor (M-CSF), but not vascular endothelial growth factor, suggesting M-CSF-dependent antitumor mechanisms. Collectively, these promising data suggest that SCHOOL TREM-1-specific peptide inhibitors have a cancer type independent, therapeutically beneficial antitumor activity and can be potentially used as a stand-alone therapy or as a component of combinational therapy for PC, NSCLC, and other solid tumors.

Clinical Association of a Soluble Triggering Receptor Expressed on Myeloid Cells-1 (sTREM-1) in Patients with Systemic Lupus Erythematosus.

A triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily with an established role in innate and adaptive immune response. We aimed to determine the plasma concentrations and clinical association of sTREM-1 in Systemic Lupus Erythematosus (SLE) patients. Plasma from 79 SLE patients and 35 normal healthy subjects were assayed for sTREM-1 and IL-6 levels using Enzyme Linked Immunosorbant Assay (ELISA). The clinical disease characteristics and serological data were prospectively assessed. Disease activity was scored using the SLE disease activity index. We detected significantly higher levels of sTREM-1 in plasma of SLE patients than the healthy control group. We also detected high sTREM-1 levels in subgroups of patients with neuropsychiatric manifestations (NPLE) and patients with the total high disease activity and NPLE activity. In addition, sTREM-l levels were significantly correlated with parameters of disease activity, i.e. SLEDAI score, IL-6, hypoalbuminemia. On the other hand, we did not find significant differences in sTREM-1 levels in relation to age, disease duration, medications, ESR, other organ system involvement, or the presence of anti-dsDNA. Our preliminary data indicated that sTREM-1 levels may be an additional useful marker of disease activity in SLE. It also highlights its importance in patients with NPLE. An additional prospective longitudinal study should be carried out to support these findings.