LSD1 Facilitates Pro-Inflammatory Polarization of Macrophages by Repressing Catalase

Abstract

The increased level of hydrogen peroxide accompanies some modes of macrophage specification and is linked to ROS-based antimicrobial activity of these phagocytes. In this study, we show that activation of toll-like receptors with bacterial components such as LPS is accompanied by the decline in transcription of hydrogen peroxide decomposing enzyme-catalase, suppression of which facilitates the polarization of human macrophages towards the pro-inflammatory phenotype. The chromatin remodeling at the CAT promoter involves LSD1 and HDAC1, but activity of the first enzyme defines abundance of the two proteins on chromatin, histone acetylation status and the CAT transcription. LSD1 inhibition prior to macrophage activation with LPS prevents CAT repression by enhancing the LSD1 and interfering with the HDAC1 recruitment to the gene promoter. The maintenance of catalase level with LSD1 inhibitors during M1 polarization considerably limits LPS-triggered expression of some pro-inflammatory cytokines and markers such as IL1β, TNFα, COX2, CD14, TLR2, and IFNAR, but the effect of LSD1 inhibitors is lost upon catalase deficiency. Summarizing, activity of LSD1 allows for the CAT repression in LPS stimulated macrophages, which negatively controls expression of some key pro-inflammatory markers. LSD1 inhibitors can be considered as possible immunosuppressive drugs capable of limiting macrophage M1 specialization.

Antagonistic action of GPS2 and KDM1A at enhancers governs alternative macrophage activation by interleukin 4

“…KDM1A and its inhibitors have been extensively studied in different cellular contexts, revealing a variety of mechanisms of action at chromatin and enhancers, both dependent and independent of KDM1A's lysine demethylation activity ( 57–59 , 73 ). Although several mechanisms have recently also been identified in M1-type macrophages ( 60–63 ) ( 74 ), they seem to be distant from those discovered in our study. It is currently not clear whether this reflects fundamental mechanistic differences of KDM1A action in M1 versus M2 contexts or rather alternative mechanisms that operate in both contexts.…”

“…In addition to all corepressor complex core subunits serving as a positive control, we identified the lysine-specific demethylase 1A (KDM1A, also known as LSD1) ( 54 ) in the GPS2-specific immunoprecipitates from both macrophage cell types (Figure 5A ). Although KDM1A has been extensively studied in multiple cell types and disease contexts ( 55–59 ), only few recent studies have explored its role in M1 macrophages ( 60–63 ), and its specific function in IL4 signaling and M2 macrophages has not yet been addressed. We thus performed ChIP-seq and compared the cistromes of GPS2, KDM1A and STAT6.…”

“…Our study advances the understanding of functions and target range of KDM1A, the first identified and probably best-studied KDM, also known as lysine-specific demethylase 1 (LSD1) ( 54 ). Although KDM1A has been extensively studied in multiple cell types and disease contexts ( 55–59 ), its specific function in IL4 signaling and M2 macrophages has not yet been addressed and only few recent studies have explored its role in M1 macrophages ( 60–63 ). Our data indicate that KDM1A opposes the GPS2 corepressor complex by acting a coactivator of IL4 signaling, as its depletion abolishes IL4-induced gene expression and increases H3K9me2/3 levels, both at the genome-wide level and within the specific IL4 target gene loci.…”

LSD1 in drug discovery: From biological function to clinical application

“…127 Additionally, LSD1 promotes catalase repression in lipopolysaccharide (LPS) stimulated macrophages, consequently exerting a negative influence on the expression of crucial proinflammatory markers. 128 Ultimately, LSD1 inhibitors possess the ability to modulate macrophage activity, thus potentially serving as immunosuppressive agents that can effectively restrict macrophage M1 polarization. Phenelzine, an LSD1 inhibitor, induced M1 phenotype-related gene expression involving CD86, and iNOS, resulting in M1 macrophage polarization.…”

“…Meanwhile, the functional interplay between poly(ADP‐ribose) polymerase 1 (PARP1) and LSD1 impacts on the transcription of superoxide dismutase 2 (SOD2) that protects human proinflammatory macrophages from oxidative‐induced cell death 127 . Additionally, LSD1 promotes catalase repression in lipopolysaccharide (LPS) stimulated macrophages, consequently exerting a negative influence on the expression of crucial proinflammatory markers 128 . Ultimately, LSD1 inhibitors possess the ability to modulate macrophage activity, thus potentially serving as immunosuppressive agents that can effectively restrict macrophage M1 polarization.…”