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

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

doi:10.1016/j.intimp.2025.114055

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

Int Immunopharmacol. 2025 Jan 10:147:114055. doi: 10.1016/j.intimp.2025.114055. Online ahead of print.

Authors

Dan Wang¹, Yimeng Zou¹, Tianqi Zhao¹, Weiyue Cao¹, Jiachi Han¹, Qing Wu¹, Zhitong Li¹, Xinyu Li¹, Peijing Liu¹, Lin Bai¹, Guiping Ren²

Affiliations

¹ Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin 150030, China.
² Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin 150030, China; Research Center of Genetic Engineering of Pharmaceuticals of Heilongjiang Province, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of Agricultural Biological Functional Gene, Northeast Agricultural University, Harbin 150030, China. Electronic address: renguiping@126.com.

PMID: 39798471
DOI: 10.1016/j.intimp.2025.114055

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.

Keywords: Asthma; Atopic dermatitis; Atopic march; FGF21; Helper T cells; JNK.