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HIF-1α Pathway Orchestration by LCN2: A Key Player in Hypoxia-Mediated Colitis Exacerbation

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Abstract

In this study, we investigated the role of hypoxia in the development of chronic inflammatory bowel disease (IBD), focusing on its impact on the HIF-1α signaling pathway through the upregulation of lipocalin 2 (LCN2). Using a murine model of colitis induced by sodium dextran sulfate (DSS) under hypoxic conditions, transcriptome sequencing revealed LCN2 as a key gene involved in hypoxia-mediated exacerbation of colitis. Bioinformatics analysis highlighted the involvement of crucial pathways, including HIF-1α and glycolysis, in the inflammatory process. Immune infiltration analysis demonstrated the polarization of M1 macrophages in response to hypoxic stimulation. In vitro studies using RAW264.7 cells further elucidated the exacerbation of inflammation and its impact on M1 macrophage polarization under hypoxic conditions. LCN2 knockout cells reversed hypoxia-induced inflammatory responses, and the HIF-1α pathway activator dimethyloxaloylglycine (DMOG) confirmed LCN2's role in mediating inflammation via the HIF-1α-induced glycolysis pathway. In a DSS-induced colitis mouse model, oral administration of LCN2-silencing lentivirus and DMOG under hypoxic conditions validated the exacerbation of colitis. Evaluation of colonic tissues revealed altered macrophage polarization, increased levels of inflammatory factors, and activation of the HIF-1α and glycolysis pathways. In conclusion, our findings suggest that hypoxia exacerbates colitis by modulating the HIF-1α pathway through LCN2, influencing M1 macrophage polarization in glycolysis. This study contributes to a better understanding of the mechanisms underlying IBD, providing potential therapeutic targets for intervention.

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The data that supports the findings of this study are available on request from the corresponding author.

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Funding

This work was financially supported by the Cultivation Fund of the National Natural Science Foundation (Grant No. qiankehe2018-5764-11).

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  1. Yun-han Yang and Fang Yan are are regarded as co-first authors.

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  1. Department of Gastroenterology, Guizhou Inflammatory Bowel Disease Research Center, National Institution of Drug Clinical Trial, Guizhou Provincial People’s Hospital, Medical College of Guizhou University, No.83 Zhongshan East Road, Guiyang, 550002, Guizhou Province, China

    Yun-han Yang, Fang Yan, Peng-shuang Shi, Liu-chan Yang & De-jun Cui

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Contributions

YHY, FY and PSS wrote the paper and conceived and designed the experiments; LCY analyzed the data; DJC collected and provided the sample for this study. All authors have read and approved the final submitted manuscript.

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Correspondence to De-jun Cui.

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All mouse experiments conducted in this study adhered to ethical principles and regulations governing the use of experimental animals, both internationally and domestically. The experimental procedures in this study have been approved by Guizhou Provincial People's Hospital, Medical College of Guizhou University (approval number: 2020413).

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Fig. S1

Silencing efficiency verification of LCN2 sequence. Note: (A) RT-qPCR measured expression levels of LCN2 in mRNA of cells from different groups. (B) Expression levels of LCN2 in the protein of cells from different groups were detected by Western blot. The cell experiments were repeated three times. Compared to the sh-NC group, P<0.05, *P<0.01.(JPG 550 KB)

Fig. S2

Animal modeling process diagram. Note: Ctrl group: no intervention, normal drinking water; DSS group: after adaptive feeding, without any treatment, directly given 2.5% DSS concentration free drinking water for 7 days; DSS+hypoxia group: after adaptive feeding, without any treatment, directly given 2.5% DSS concentration free drinking water for 7 days, during which cultured in a hypoxic incubator. Transcriptional sequencing was performed on colonic tissues of the above three groups, and differential analysis was conducted between the Ctrl group vs DSS group and DSS group vs DSS+hypoxia group. DSS+hypoxia+Sh-NC group: targeted injection of empty lentivirus, after 7 days of recovery, given 2.5% DSS concentration free drinking water for 7 days, during which cultured in a hypoxic incubator; DSS+hypoxia+Sh-LCN2 group: targeted injection of LCN2-silencing lentivirus, after 7 days of recovery, given 2.5% DSS concentration free drinking water for 7 days, during which cultured in a hypoxic incubator; DSS+hypoxia+Sh-LCN2+DMOG group: targeted injection of LCN2-silencing lentivirus, after 7 days of recovery, given 2.5% DSS concentration free drinking water for 7 days, and daily administered 10mg/kg DMOG by gavage, during which cultured in a hypoxic incubator. Signs and symptoms were observed daily during the culture period, and biochemical tests were performed after euthanasia (JPG 3122 KB)

Fig. S3

The intersection of transcriptome sequencing results of two groups. Note: (A) Venn diagram of transcriptome sequencing results of two groups; (B) 12 differentially expressed genes in the intersection; (C) Heatmap showing the expression of the 12 differentially expressed genes in the two groups; (D) Interactions among the 12 differentially expressed genes. The LCN2 gene, a key gene identified in the previous analysis, is highlighted in red. (JPG 640 KB)

Fig. S4

CRISPR/Cas9 gene editing and knockout process of LCN2 and validation of knockout efficacy. Note: (A) Workflow of CRISPR/Cas9 gene editing and knockout of LCN2; (B) PCR products of LCN2-KO cells and β-actin from different groups run on agarose gel (Lane 1 = 100 bp ladder; Lane 2 = β-actin of RAW264.7-Scr cells; Lane 3 = β-actin of LCN2-KO cells; Lane 4 = LCN2 of RAW264.7-Scr cells; Lane 5 = LCN2 of LCN2-KO cells); (C) Immunofluorescence staining for the expression of LCN2. Compared to the KO-NC-scr group, P<0.05, *P<0.01. Bar=100 μm.(JPG 2726 KB)

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Yang, Yh., Yan, F., Shi, Ps. et al. HIF-1α Pathway Orchestration by LCN2: A Key Player in Hypoxia-Mediated Colitis Exacerbation. Inflammation 47, 1491–1519 (2024). https://doi.org/10.1007/s10753-024-01990-y

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