Lysine-specific demethylase 1 (LSD1) serves as an potential epigenetic determinant to regulate inflammatory responses...

It is well-established that lysine-specific demethylase 1 (LSD1) is the first identified histone demethylase. Based on its demethylase enzymatic activity, LSD1 plays a pivotal role in vast range of cellular processes and cancers, but the understanding of its effects on inflammation is relatively limited. Using in vivo models of lipopolysaccharide (LPS)-induced inflammation and in vitro assays in mouse mammary epithelial cells, we identified the novel regulatory roles and underlying mechanisms of LSD1 on LPS-induced mastitis. Mammary gland and cells were collected for the following experiments after treatment. Histological changes were determined by H&E. Western blot analysis was used to detect the protein expression. ELISA and real-time PCR were used to evaluate protein and mRNA expression of inflammatory genes. Our results showed that LPS treatment resulted in a significant increase in LSD1 protein expression. GSK-LSD1 is a selective inhibitor of LSD1 enzyme activity. Treatment of mice with GSK-LSD1 inhibited LSD1 activity, reduced inflammatory cells recruitment to tissues and attenuated LPS-induced damage in mammary gland. Mechanistic investigations suggested that LSD1 inhibition led to the increase of histone H3K4me2 and H3K9me2. Furthermore, GSK-LSD1 inhibition of LSD1 further inhibited nuclear factor κ-B (NF-κB) signaling cascades, and subsequently inhibited the production of cytokines (TNF-α, IL-6 and IL-1β) in mammary gland. Taken together, our data reveal LSD1 as a potential regulator of inflammation and improve our understanding of epigenetic control on inflammation.