Lipocalin-2 in neutrophils induces ferroptosis in septic cardiac dysfunction via increasing labile iron pool of cardiomyocytes

Huang, Yuxue; Zhang, Ning; Xie, Cuiping; You, Yayu; Guo, Lei; Ye, Feiming; Xie, Xing; Wang, Jianan

doi:10.3389/fcvm.2022.922534

Cited by 10 publications

(6 citation statements)

References 53 publications

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“…S2D). In agreement with our data, the secretion of LCN2 by neutrophils had been shown before ( 26 , 38 ). To evaluate the functional role of LCN2 + neutrophils in aGVHD, BALB/c recipients underwent allo-HCT, followed by transfer of LCN2-overexpressing Hoxb8 progenitor cells or empty vector control cells.…”

Section: Resultssupporting

confidence: 94%

“…Furthermore, because the administration of recombinant LCN2 protected mice from aGVHD, treatment with LCN2 could be an alternative to cell-based therapy. Previously published data showed increased LCN2 secretion from neutrophils isolated from murine blood upon exposure to LPS in vitro ( 38 ), which we confirmed in BM-derived neutrophils. An additional mechanism of LCN2 induction is the release of IFN-γ and tumor necrosis factor–α ( 51 ).…”

Section: Discussionsupporting

confidence: 88%

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Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease

Czech,

Schneider,

Peltokangas

et al. 2024

Sci. Transl. Med.

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Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), for which therapeutic options are limited. Strategies to promote intestinal tissue tolerance during aGVHD may improve patient outcomes. Using single-cell RNA sequencing, we identified a lipocalin-2 (LCN2)–expressing neutrophil population in mice with intestinal aGVHD. Transfer of LCN2-overexpressing neutrophils or treatment with recombinant LCN2 reduced aGVHD severity, whereas the lack of epithelial or hematopoietic LCN2 enhanced aGVHD severity and caused microbiome alterations. Mechanistically, LCN2 induced insulin-like growth factor 1 receptor (IGF-1R) signaling in macrophages through the LCN2 receptor SLC22A17, which increased interleukin-10 (IL-10) production and reduced major histocompatibility complex class II (MHCII) expression. Transfer of LCN2-pretreated macrophages reduced aGVHD severity but did not reduce graft-versus-leukemia effects. Furthermore, LCN2 expression correlated with IL-10 expression in intestinal biopsies in multiple cohorts of patients with aGVHD, and LCN2 induced IGF-1R signaling in human macrophages. Collectively, we identified a LCN2-expressing intestinal neutrophil population that reduced aGVHD severity by decreasing MHCII expression and increasing IL-10 production in macrophages. This work provides the foundation for administration of LCN2 as a therapeutic approach for aGVHD.

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Section: Resultssupporting

confidence: 94%

Section: Discussionsupporting

confidence: 88%

Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease

Czech,

Schneider,

Peltokangas

et al. 2024

Sci. Transl. Med.

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“…Detection of LCN2 levels in blood or other biological specimens may help in the early diagnosis of sepsis and monitoring of disease progression. [ 22 ] Role of LCN2 in immune response: Further studies have explored the specific role of LCN2 in immune response. LCN2 may be involved in the pathogenesis of sepsis by regulating the inflammatory process and influencing the activity of immune cells.…”

Section: Discussionmentioning

confidence: 99%

LCN2 and ELANE overexpression induces sepsis

Wang,

Han,

Dong

et al. 2024

Medicine

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Sepsis is a syndrome characterized by a systemic inflammatory response due to the invasion of pathogenic microorganisms. The relationship between Lipocalin-2 (LCN2), elastase, neutrophil expressed (ELANE) and sepsis remains unclear. The sepsis datasets GSE137340 and GSE154918 profiles were downloaded from gene expression omnibus generated from GPL10558. Batch normalization, differentially expressed Genes (DEGs) screening, weighted gene co-expression network analysis (WGCNA), functional enrichment analysis, Gene Set Enrichment Analysis (GSEA), immune infiltration analysis, construction and analysis of protein–protein interaction (PPI) networks, Comparative Toxicogenomics Database (CTD) analysis were performed. Gene expression heatmaps were generated. TargetScan was used to screen miRNAs of DEGs. 328 DEGs were identified. According to Gene Ontology (GO), in the Biological Process analysis, they were mainly enriched in immune response, apoptosis, inflammatory response, and immune response regulation signaling pathways. In cellular component analysis, they were mainly enriched in vesicles, cytoplasmic vesicles, and secretory granules. In Molecular Function analysis, they were mainly concentrated in hemoglobin binding, Toll-like receptor binding, immunoglobulin binding, and RAGE receptor binding. In Kyoto Encyclopedia of Genes and Genomes (KEGG), they were mainly enriched in NOD-like receptor signaling pathway, Toll-like receptor signaling pathway, TNF signaling pathway, P53 signaling pathway, and legionellosis. Seventeen modules were generated. The PPI network identified 4 core genes (MPO, ELANE, CTSG, LCN2). Gene expression heatmaps revealed that core genes (MPO, ELANE, CTSG, LCN2) were highly expressed in sepsis samples. CTD analysis found that MPO, ELANE, CTSG and LCN2 were associated with sepsis, peritonitis, meningitis, pneumonia, infection, and inflammation. LCN2 and ELANE are highly expressed in sepsis and may serve as molecular targets.

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“…Cell culture and treatment. To investigate the mechanism of sepsis-induced myocardial injury, H9c2 rat cardiomyocytes were selected for use in the present study (21,22). Dulbecco's modified Eagle's medium (DMEM; Thermo Fisher Scientific, Inc.) containing 10% FBS (Thermo Fisher Scientific, Inc.) was used to cultivate H9c2 cells, which were supplied by the American Type Culture Collection, at 37˚C with 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Parecoxib attenuates inflammation injury in septic H9c2 cells by regulating the MAPK signaling pathway

et al. 2023

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Parecoxib, a non-steroidal anti-inflammatory drug, has been reported to possess protective effects against sepsis. However, its detailed role and underlying mechanisms in septic cardiomyopathy remain unclear. Therefore, the goal of the present study was to clarify the function and to investigate the mechanisms of parecoxib in lipopolysaccharide (LPS)-treated H9c2 rat cardiomyocytes. TNF-α, IL-1β and IL-6 expression levels in parecoxib-treated H9c2 cells stimulated with LPS were assessed using ELISA. Parecoxib-treated H9c2 cells stimulated with LPS were tested for viability using the Cell Counting Kit-8 assay. Western blotting analysis and 5-ethynyl-2'-deoxyuridine were used to evaluate cell proliferation. Apoptosis was assessed using TUNEL and western blotting. To assess the protein expression of the MAPK signaling pathway, western blotting was performed. The data showed that parecoxib significantly and dose-dependently reduced the inflammatory responses of LPS-treated H9c2 cells. Parecoxib also significantly and dose-dependently increased the proliferation and inhibited the apoptosis of LPS-treated H9c2 cells. In addition, parecoxib significantly suppressed the activation of the MAPK (p38, JNK and ERK) signaling pathway. The current study indicated that parecoxib could be a viable therapeutic option for septic cardiomyopathy.

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Lipocalin-2 in neutrophils induces ferroptosis in septic cardiac dysfunction via increasing labile iron pool of cardiomyocytes

Cited by 10 publications

References 53 publications

Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease

Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease

LCN2 and ELANE overexpression induces sepsis

Parecoxib attenuates inflammation injury in septic H9c2 cells by regulating the MAPK signaling pathway

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