JMJD3 downregulates IL4i1 aggravating lipopolysaccharide‐induced acute lung injury via H3K27 and H3K4 demethylation

Abstract

The pro‐inflammation M1 to anti‐inflammation M2 macrophage ratio contribute to the severity of lipopolysaccharide (LPS)‐induced acute lung injury (ALI). JMJD3 aggravates the inflammatory reaction through affecting epigenetic modification and macrophage's phenotype to deteriorate ALI. To explore the mechanism underlying the upregulation of the macrophage M1/M2 ratio through JMJD3, we developed an ALI mouse model using intratracheal LPS, LPS‐stimulated RAW 264.7 cells, and inhibited JMJD3 using GSK‐J4. H3K27me3 and H3K4me3 were investigated as JMJD3‐mediated epigenetic alteration sites in vivo and in vitro. C/EBPβ and KDM5A were validated as linking factors between H3K27 and H3K4. IL4i1 was investigated as a JMJD3‐mediated targeted gene to regulate the macrophage M1/M2 ratio. Chromatin immunoprecipitation was used to evaluate the relationship between H3K27me3 and C/ebpβ, C/EBPβ and Kdm5a, H3K4me3 and Il4i1. Inhibiting JMJD3 with GSK‐J4 can relieve inflammation and pathological performance in ALI. JMJD3 can reduce IL4i1 expression to increase the macrophage M1/M2 ratio and aggravated ALI which process was mediated via JMJD3‐indcued H3K27me3 and H3K4me3 demethylation, latter H3K4me3 demethylation inhibited IL4i1 transcription. Inhibiting JMJD3 with GSK‐J4 can increase IL4i1 expression, subsequently decreasing the expressions of M1 and increasing of M2 in vivo. The over‐expression IL4i1 in LPS‐stimulated macrophage or inhibiting JMJD3 with GSK‐J4 can both reverse the increase of the macrophage M1/M2 ratio in vitro. C/EBPβ and KDM5A were upregulated by LPS simulation, which linked JMJD3‐induced H3K27‐H3K4 demethylation. JMJD3 inhibited IL4i1 to increase the macrophage M1/M2 phenotype ratio and aggravate LPS‐induced ALI. Using GSK‐J4 to inhibit JMJD3 may facilitate the treatment of LPS‐induced ALI.

IL4I1 in M2-like macrophage promotes glioma progression and is a promising target for immunotherapy

“…IL4I1 has been associated mainly with the immunoregulation and oncogenic properties of multiple tumors, which could be attributed to its ability to convert amino acids, generate H 2 O 2 , or exhibit an enzyme-independent function (42, 43). Specifically, IL4I1 has been demonstrated to oxidize phenylalanine into phenylpyruvic acid and H 2 O 2 , as well as to convert tyrosine and Trp into hydroxyphenylpyruvic (HPP) acid and I3P, respectively (44,45). Previous studies have shown that IL4I1 could augment growth vitality of cancer cells and diminish the motility of CD8+ T cells through the I3P-aryl hydrocarbon receptor (AHR) axis (17).…”