H3K27 tri-demethylase JMJD3 inhibits macrophage apoptosis by promoting ADORA2A in lipopolysaccharide-induced acute lung injury

Acute lung injury (ALI) is a common critical disease, which is characterized by an uncontrolled, acute inflammatory response, diffuse lung damage and ultimately directly deteriorates into acute respiratory distress syndrome. The number of pro-inflammatory macrophages is related to the severity of ALI. Up-regulation of lipopolysaccharide (LPS)-activated macrophage apoptosis can reduce the pro-inflammatory reactions. Jumonji domain-containing protein D3 (JMJD3)-mediated histone 3 lysine 27 trimethylation (H3K27me3) demethylation may promote the pro-inflammatory response of macrophages under LPS stimulation. However, the mechanism of JMJD3 affecting macrophage apoptosis is still not clear. To explore this gap in knowledge, the ALI mice model with intratracheal administration of LPS and RAW264.7 cells with LPS stimulation were used as in vivo and in vitro experiments. The expression of JMJD3 and H3K27me3 and their cellular localization were analysed in lung tissue. Apoptosis was evaluated using TUNEL staining and flow cytometry. Expression of H3K27me3, ADORA2A and C/EBPβ were compared among different treatments and chromatin immunoprecipitation was performed to investigate the regulatory relationship. Our study showed that JMJD3 expression was upregulated in LPS-induced ALI mice and RAW264.7 cells. JMJD3-indued H3K27me3 demethylation inhibited caspase-3 cleavage by upregulating ADORA2A to decrease LPS-stimulated macrophage apoptosis and promoted the inflammatory reaction. This H3K27me3 demethylation also increased C/EBPβ expression, which may enhance ADORA2A expression further. Besides, inhibiting ADORA2A can also promote LPS-limited macrophage apoptosis. Moreover, the inhibition of JMJD3 in vivo and in vitro relieved the inhibition of macrophage apoptosis thus leading to the resolution of the inflammation. JMJD3 might inhibit macrophage apoptosis by promoting ADORA2A expression in LPS-induced ALI. [Image: see text]