巨噬细胞中成纤维细胞生长因子受体 4 的缺乏会促进 M1 极化,从而加重实验性结肠炎。

IF 4.8 3区 医学 Q2 CELL BIOLOGY Inflammation Research Pub Date : 2024-09-01 Epub Date: 2024-07-10 DOI:10.1007/s00011-024-01910-8
Luyao Shen, Cong Wang, Ran Ren, Xudong Liu, Dongqin Zhou, Yu Chen, Yu Zhou, Juan Lei, Yang Xiao, Nan Zhang, Huakan Zhao, Yongsheng Li
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引用次数: 0

摘要

目的和设计:令人信服的证据表明,失调的巨噬细胞可能在炎症性肠病(IBD)的炎症驱动过程中发挥关键作用。成纤维细胞生长因子(FGF)-19 是回肠肠细胞分泌的对胆汁酸的反应因子,研究发现,与健康人相比,IBD 患者的成纤维细胞生长因子-19 明显降低,而且与腹泻的严重程度呈负相关。本研究旨在探讨 FGF19 信号传导对巨噬细胞极化的潜在影响及其在 IBD 发病机制中的参与作用:方法:利用葡聚糖硫酸钠(DSS)诱导的小鼠结肠炎模型来复制人类 IBD 的病理。方法:利用葡聚糖硫酸钠(DSS)诱导的小鼠结肠炎模型复制人类 IBD 的病理。结肠炎的严重程度是通过疾病活动指数(DAI)和组织病理学染色来测量的。研究采用了多种技术,如 Western 印迹、定量 PCR、流式细胞术和 ELISA,以评估极化和炎症基因的表达:结果:骨髓特异性 FGFR4 缺乏会加重 DSS 小鼠模型中的结肠炎。骨髓源性巨噬细胞(BMDMs)中FGFR4的缺失或抑制使巨噬细胞偏向M1极化。转录组测序数据分析显示,巨噬细胞中的 FGFR4 基因缺失会显著增加补体途径的活性,从而导致 LPS 引发的炎症反应增强。从机制上讲,巨噬细胞中的FGFR4基因敲除通过上调核因子-κB(NF-κB)-五肽3(PTX3)通路促进了补体激活和炎症反应。此外,FGF19 还通过激活炎性巨噬细胞中的 FGFR4 来抑制这些通路并减轻炎症反应。肝脏特异性过表达 FGF19 还能减轻 DSS 在体内诱导的炎症反应:我们的研究强调了 FGF19-FGFR4 信号在巨噬细胞极化和 IBD 发病机制中的重要作用,为 IBD 提供了一个潜在的新治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Fibroblast growth factor receptor 4 deficiency in macrophages aggravates experimental colitis by promoting M1-polarization.

Objective and design: Compelling evidence indicates that dysregulated macrophages may play a key role in driving inflammation in inflammatory bowel disease (IBD). Fibroblast growth factor (FGF)-19, which is secreted by ileal enterocytes in response to bile acids, has been found to be significantly lower in IBD patients compared to healthy individuals, and is negatively correlated with the severity of diarrhea. This study aims to explore the potential impact of FGF19 signaling on macrophage polarization and its involvement in the pathogenesis of IBD.

Methods: The dextran sulfate sodium (DSS)-induced mouse colitis model was utilized to replicate the pathology of human IBD. Mice were created with a conditional knockout of FGFR4 (a specific receptor of FGF19) in myeloid cells, as well as mice that overexpressing FGF19 specifically in the liver. The severity of colitis was measured using the disease activity index (DAI) and histopathological staining. Various techniques such as Western Blotting, quantitative PCR, flow cytometry, and ELISA were employed to assess polarization and the expression of inflammatory genes.

Results: Myeloid-specific FGFR4 deficiency exacerbated colitis in the DSS mouse model. Deletion or inhibition of FGFR4 in bone marrow-derived macrophages (BMDMs) skewed macrophages towards M1 polarization. Analysis of transcriptome sequencing data revealed that FGFR4 deletion in macrophages significantly increased the activity of the complement pathway, leading to an enhanced inflammatory response triggered by LPS. Mechanistically, FGFR4-knockout in macrophages promoted complement activation and inflammatory response by upregulating the nuclear factor-κB (NF-κB)-pentraxin3 (PTX3) pathway. Additionally, FGF19 suppressed these pathways and reduced inflammatory response by activating FGFR4 in inflammatory macrophages. Liver-specific overexpression of FGF19 also mitigated inflammatory responses induced by DSS in vivo.

Conclusion: Our study highlights the significance of FGF19-FGFR4 signaling in macrophage polarization and the pathogenesis of IBD, offering a potential new therapeutic target for IBD.

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来源期刊
Inflammation Research
Inflammation Research 医学-免疫学
CiteScore
9.90
自引率
1.50%
发文量
134
审稿时长
3-8 weeks
期刊介绍: Inflammation Research (IR) publishes peer-reviewed papers on all aspects of inflammation and related fields including histopathology, immunological mechanisms, gene expression, mediators, experimental models, clinical investigations and the effect of drugs. Related fields are broadly defined and include for instance, allergy and asthma, shock, pain, joint damage, skin disease as well as clinical trials of relevant drugs.
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