LINC00461 promotes macrophage M1 polarization by inhibiting KLF4 transcription

IF 2.3 4区医学 Q3 IMMUNOLOGY

Immunobiology Pub Date : 2025-07-01 DOI:10.1016/j.imbio.2025.153104

Bicong Gao , Kaitong Jia , You Ya , Rui Tian , Xiaochen Wang , Zheng Huang , Feng Gao

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Abstract

Background

Macrophage polarization is a complex process whereby macrophages differentiate into M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes, mediating distinct and often opposing functions in immunity and tissue repair.

Methods

We analyzed LINC00461 expression in M1- and M2-polarized macrophages using qPCR. Functional assays (in vitro and in vivo) were performed to assess the effects of LINC00461 knockdown on cytokine secretion. RNA-seq, bisulfite sequencing, and chromatin immunoprecipitation (ChIP) were used to explore the mechanism involving Kruppel-like factor 4 (KLF4) and DNA methylation.

Results

LINC00461 levels were elevated in M1 macrophages and reduced in M2 macrophages. Knockdown of LINC00461 attenuated pro-inflammatory cytokine release (e.g., IL-1β, TNF-α) in M1 cells and promoted anti-inflammatory cytokine secretion (e.g., IL-10, TGF-β) in M2 cells. Mechanistically, LINC00461 knockdown upregulated KLF4 transcription, a key M2 polarization regulator. LINC00461 recruited DNA methyltransferases to induce hypermethylation of the KLF4 promoter, suppressing KLF4 expression and driving M1 polarization.

Conclusion

Our findings establish a functional link between LINC00461, KLF4 methylation, and macrophage polarization, providing insights into the epigenetic regulation of inflammatory responses.

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LINC00461通过抑制KLF4转录促进巨噬细胞M1极化

巨噬细胞极化是一个复杂的过程，巨噬细胞分化为M1（促炎）或M2（抗炎）表型，在免疫和组织修复中介导不同且通常相反的功能。方法采用qPCR方法分析LINC00461在M1和m2极化巨噬细胞中的表达。通过体外和体内功能测定来评估LINC00461基因敲低对细胞因子分泌的影响。利用RNA-seq、亚硫酸盐测序和染色质免疫沉淀（ChIP）技术探讨Kruppel-like factor 4 （KLF4）和DNA甲基化相关的机制。结果M1巨噬细胞中linc00461水平升高，M2巨噬细胞中linc00461水平降低。敲低LINC00461可减弱M1细胞中促炎细胞因子（如IL-1β、TNF-α）的释放，促进M2细胞中抗炎细胞因子（如IL-10、TGF-β）的分泌。从机制上讲，LINC00461的敲低上调了KLF4的转录，这是一个关键的M2极化调节因子。LINC00461募集DNA甲基转移酶诱导KLF4启动子超甲基化，抑制KLF4表达并驱动M1极化。结论我们的研究结果建立了LINC00461、KLF4甲基化和巨噬细胞极化之间的功能联系，为炎症反应的表观遗传调控提供了新的见解。

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

Immunobiology 医学-免疫学

CiteScore

5.00

自引率

3.60%

发文量

108

审稿时长

55 days

期刊介绍： Immunobiology is a peer-reviewed journal that publishes highly innovative research approaches for a wide range of immunological subjects, including • Innate Immunity, • Adaptive Immunity, • Complement Biology, • Macrophage and Dendritic Cell Biology, • Parasite Immunology, • Tumour Immunology, • Clinical Immunology, • Immunogenetics, • Immunotherapy and • Immunopathology of infectious, allergic and autoimmune disease.