LINC00461 promotes macrophage M1 polarization by inhibiting KLF4 transcription

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.

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.

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.

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