TREM-1 Contributes to Inflammation in IgA Nephropathy

Zhao, Yanfeng; Zhu, Li; Liu, Lijun; Shi, Sufang; Lv, Jicheng; Zhang, Hong

doi:10.1159/000485622

Cited by 9 publications

(12 citation statements)

References 29 publications

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“…The activation of TREM1 signaling pathway would promote the release of multiple cytokines and chemokines, resulted in amplification of inflammatory responses [30]. Our previous studies found that IgA1-containing immune complexes from IgAN patients could upregulate the expression of TREM1 in cultured mesangial cells and elevated level of its soluble form (sTREM1) in the urine of IgAN patients was correlated with severe clinical and pathological manifestations [31, 32]. Besides, a recent study showed that the increase of TREM1 mRNA expression level in peripheral leukocytes of patients with Alzheimer’s disease was significantly correlated with the hypomethylation of the gene promoter [33].…”

Section: Discussionmentioning

confidence: 99%

Monozygotic Twins Discordant for Immunoglobulin A Nephropathy Display Differences in DNA Methylation and Gene Expression

et al. 2020

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Introduction: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis. It involves both genetic and environmental factors, among which DNA methylation, the most studied epigenetic modification, was shown to play a role. Here, we assessed genome-wide DNA methylation and gene expression profiles in 2 pairs of IgAN-discordant monozygotic (MZ) twins, in order to characterize methylation changes and their potential influences on gene expression in IgAN. Methods: Genome-wide DNA methylation and gene expression profiles were evaluated in peripheral blood mononuclear cells obtained from 2 IgAN-discordant MZ twins. Differentially methylated regions (DMRs) and differentially expressed genes (DEGs) were detected, and an integrated analysis was performed. Finally, functional enrichment analysis was done for DMR-associated genes and DEGs. Results: Totally 521 DMRs were detected for 2 IgAN-discordant MZ twins. Among them, 9 DMRs were found to be mapped to genes that differentially expressed in 2 MZ twins, indicating the potential regulatory mechanisms of expression for these 9 genes (MNDA, DYSF, IL1R2, TLR6, TREML2, TREM1, IL32, S1PR5, and ADGRE3) in IgAN. Biological process analysis of them showed that they were mostly involved in the immune system process. Functional enrichment analysis of DEGs and DMR-associated genes both identified multiple pathways relevant to inflammatory and immune responses. And DMR-associated genes were significantly enriched in terms related to T-cell function. Conclusions: Our findings indicate that changes in DNA methylation patterns were involved in the pathogenesis of IgAN. Nine target genes detected in our study may provide new ideas for the exploration of molecular mechanisms of IgAN.

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Section: Discussionmentioning

confidence: 99%

Monozygotic Twins Discordant for Immunoglobulin A Nephropathy Display Differences in DNA Methylation and Gene Expression

et al. 2020

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“…TREM-1 could not only mediate sepsis-related kidney damage but also contribute to inflammation in IgA nephropathy, which has been detected by urinalysis 21 . sTREM-1 levels were also shown to be significantly increased in hemodialysis patients and positively correlated with CRP and TNF-α levels 22 .…”

Section: Discussionmentioning

confidence: 96%

TREM-1 promoted apoptosis and inhibited autophagy in LPS-treated HK-2 cells through the NF-κB pathway

Pan¹,

Li²,

Wu³

et al. 2021

Int. J. Med. Sci.

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Triggering receptor expressed by myeloid cells (TREM-1) is an amplifier of inflammatory responses triggered by bacterial or fungal infection. Soluble TREM-1 (sTREM-1) expression was found to be upregulated in sepsis-associated acute kidney injury (SA-AKI) and predicted to be a potential biomarker. However, the mechanism remains unclear. The human kidney-2 (HK-2) cell line was treated with lipopolysaccharide (LPS) and used to examine the potential roles of TREM-1 in apoptosis and autophagy. A cell viability assay was employed to assess the number of viable cells and as a measure of the proliferative index. The concentrations of sTREM-1, interleukin (IL)-1β, tumor necrosis factor-α (TNFα) and IL-6 in cell-free culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA). Western blot analysis was performed to analyze apoptosis, autophagy and the relevant signaling pathways. The results suggested that TREM-1 overexpression after LPS treatment decreased proliferation and increased apoptosis. The concentrations of sTREM-1, IL-1β, TNFα and IL-6 in cell-free culture supernatants were increased in the TREM-1 overexpression group after LPS treatment. Expression of the antiapoptotic gene Bcl-2 was downregulated in the TREM-1 overexpression group, while that of the proapoptotic genes Bax, cleaved caspase-3 and cleaved caspase-9 was upregulated. Overexpression of TREM-1 downregulated expression of the autophagy genes Beclin-1, Atg-5 and LC3b and increased the gene expression of p62, which inhibits autophagy. Conversely, treatment with TREM-1-specific shRNA had the opposite effects. The nuclear factor-κB (NF-κB) signaling pathway (P-p65/p65 and P-IκBα/IκBα) in LPS-induced HK-2 cells was regulated by TREM-1. In summary, TREM-1 promoted apoptosis and inhibited autophagy in HK-2 cells in the context of LPS exposure potentially through the NF-κB pathway.

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“…TREM-1 is expressed in many kidney cells, including renal mesangial cells ( Zhao et al, 2018 ), tubular epithelial cells ( Maiese et al, 2019 ; Pan et al, 2021 ), and kidney macrophages ( Campanholle et al, 2013 ; Zhang et al, 2019a ; Zhang et al, 2019b ). TREM-1 is also expressed in endothelial cells ( Gibot et al, 2019 ), although the role of TREM-1 in renal endothelial cells is not very well known.…”

Section: Discussionmentioning

confidence: 99%

Extracellular CIRP induces acute kidney injury via endothelial TREM-1

Siskind

Zhang²,

Wang³

2022

Front. Physiol.

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Introduction: Acute kidney injury is associated with elevated serum levels of extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern released during ischemia/reperfusion injury, hemorrhagic shock, and sepsis. It is unknown if circulating eCIRP and eCIRP-induced activation of receptor triggering receptor expressed on myeloid cells-1 (TREM-1), expressed on endothelial cells, play an important role in the pathogenesis of AKI.Methods: Male B6 wild-type (WT) and TREM-1−/− mice were subjected to intravenous injection of recombinant murine (rm) CIRP. Serum, urine, and renal tissue were collected 6 h later for analysis. Additionally, primary human renal glomerular endothelial cells (HRGEC) were stimulated in vitro with rmCIRP after pretreatment with M3, a novel inhibitory peptide of TREM-1, or vehicle. Supernatants and cells were collected 20 h after stimulation.Results: After injection with rmCIRP, WT mice had a significant increase in serum levels of BUN, creatinine, and NGAL compared to control. Additionally, NGAL was significantly increased in the urine of rmCIRP-injected mice, suggesting that circulating eCIRP can directly induce AKI. The levels of TREM-1 mRNA in the kidneys, as well as soluble (s) TREM-1 released into the serum and urine, were significantly increased in rmCIRP-injected mice. TREM-1−/− mice injected with rmCIRP had attenuated AKI, indicated by significantly decreased serum BUN, creatinine, and NGAL, and renal mRNA expression of NGAL and KIM-1 compared to WT mice. TREM-1−/− mice also had attenuated endothelial activation, with decreased mRNA and protein expression of ICAM-1 in renal tissue. HRGEC stimulated with rmCIRP in vitro had significant increases in cytokine production and sTREM-1 release, which was attenuated in cells treated with M3.Conclusion: Activation of renal TREM-1 with circulating eCIRP is sufficient to cause AKI. Elevated levels of eCIRP may be critical for the development of AKI under conditions such as ischemia/reperfusion injury, hemorrhagic shock, and sepsis. Mice deficient in the TREM-1 receptor have attenuated AKI and reduced endothelial cell activation after injection of rmCIRP. TREM-1 inhibition with M3 attenuates HRGEC activation after eCIRP stimulation. Targeting eCIRP activation of TREM-1 may provide a novel and effective treatment for AKI.

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TREM-1 Contributes to Inflammation in IgA Nephropathy

Cited by 9 publications

References 29 publications

Monozygotic Twins Discordant for Immunoglobulin A Nephropathy Display Differences in DNA Methylation and Gene Expression

Monozygotic Twins Discordant for Immunoglobulin A Nephropathy Display Differences in DNA Methylation and Gene Expression

TREM-1 promoted apoptosis and inhibited autophagy in LPS-treated HK-2 cells through the NF-κB pathway

Extracellular CIRP induces acute kidney injury via endothelial TREM-1

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