Fibroblast growth factor 21 alleviated atopic march by inhibiting the differentiation of type 2 helper T cells

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-02-06 DOI:10.1016/j.intimp.2025.114055

Dan Wang , Yimeng Zou , Tianqi Zhao , Weiyue Cao , Jiachi Han , Qing Wu , Zhitong Li , Xinyu Li , Peijing Liu , Lin Bai , Guiping Ren

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引用次数: 0

Abstract

Background

The blood FGF21 expression has been previously suggested to increase in patients developing atopic dermatitis (AD) and asthma. However, its impact on atopic march is rarely analyzed. The present work focused on investigating the role of Fibroblast Growth Factor 21(FGF21) in atopic march mice and its underlying mechanisms.

Methods

The models were induced with Diisononyl phthalate (DINP) and OVA in wild-type C57BL/6 and FGF21^−/− mice. RAW264.7 cells were induced by LPS with/without FGF21 or KLB-SiRNA for in vitro analyses.

Results

The data indicated that there were more severe allergic reactions including IgE levels and the proportion of mast cells in the blood of FGF21^−/− mice in relative to WT model mice during the progression from AD to asthma. However, exogenous administration of FGF21 inhibited allergies. In this study, we reported that FGF21 mitigated AD-like lesions and Th1/2 or Th17/Treg cell imbalance in AD mice, and significantly decreased TSLP, IL-33, IL-4, IL-5, IL-13 and IL-17A expression on skin. During the asthma phase, FGF21 improved airway remodeling by downgrading inflammatory factors IL-4, IL-5, IL-13 and IL-17A; fibrotic markers α-SMA and Collagen I; and oxidative products MDA and ROS in wild-type model mice. Compared with WT model mice, the adverse consequences were aggravated in FGF21^−/− asthmatic mice. From the mechanistic perspective, FGF21 suppressed NF-κB/NLRP3, TGF-β1/Smad3 and JNK signaling pathways and increased Nrf2 expression in vivo and in vitro. In addition, β-Klotho knockdown attenuated the ameliorative impact of FGF21 on cellular damage. Blocking AMPKα in the LPS-treated RAW264.7 cells inhibited the reduction of FGF21 and the phosphorylation of JNK.

Conclusions

To conclude, FGF21 alleviated atopic march by inhibiting Th2/17 immune response, and reduced airway remodeling by regulating NF-κB/NLRP3, TGF-β1/Smad3 and AMPKα/JNK pathways. Moreover, this study provides a rationale and novel ideas for applying FGF21 in treating AD and asthma.

查看原文本刊更多论文

成纤维细胞生长因子21通过抑制2型辅助性T细胞的分化来减轻特应性行军。

背景：血液中FGF21的表达在特应性皮炎（AD）和哮喘患者中升高。然而，其对特应性行军的影响却很少被分析。本研究旨在探讨成纤维细胞生长因子21（FGF21）在特应性行军小鼠中的作用及其潜在机制。方法：以野生型C57BL/6和FGF21-/-小鼠为模型，采用邻苯二甲酸二异壬酯（DINP）和卵细胞（OVA）制备模型。用LPS诱导RAW264.7细胞（含/不含FGF21或KLB-SiRNA）进行体外分析。结果：数据显示，在AD向哮喘发展过程中，FGF21-/-小鼠血液中IgE水平和肥大细胞比例等过敏反应较WT模型小鼠更为严重。然而，外源性给药FGF21抑制过敏。在本研究中，我们报道了FGF21减轻AD小鼠AD样病变和Th1/2或Th17/Treg细胞失衡，并显著降低皮肤上TSLP、IL-33、IL-4、IL-5、IL-13和IL-17A的表达。在哮喘期，FGF21通过降低炎症因子IL-4、IL-5、IL-13和IL-17A改善气道重塑；纤维化标志物α-SMA和I型胶原；和氧化产物MDA和ROS。与WT模型小鼠相比，FGF21-/-哮喘小鼠的不良反应加重。从机制上看，FGF21在体内外均抑制NF-κB/NLRP3、TGF-β1/Smad3、JNK信号通路，增加Nrf2表达。此外，β-Klotho敲低可减弱FGF21对细胞损伤的改善作用。在lps处理的RAW264.7细胞中阻断AMPKα抑制FGF21的降低和JNK的磷酸化。结论：综上所述，FGF21通过抑制Th2/17免疫应答减轻特应性行军，并通过调节NF-κB/NLRP3、TGF-β1/Smad3和AMPKα/JNK通路减少气道重塑。此外，本研究为FGF21治疗AD和哮喘提供了理论基础和新思路。

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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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.