Leukemia inhibitory factor drives transcriptional programs that promote lipid accumulation and M2 polarization in macrophages

Abstract

Abstract Leukemia inhibitory factor, a member of the interleukin-6 cytokine family, plays a central role in homeostasis and disease. Interestingly, some of the pleiotropic effects of leukemia inhibitory factor have been attributed to the modulation of macrophage functions although the molecular underpinnings have not been explored at a genome-wide scale. Herein, we investigated leukemia inhibitory factor–driven transcriptional changes in murine bone marrow–derived macrophages by RNA sequencing. In silico analyses revealed a selective and time-dependent remodeling of macrophage gene expression programs associated with lipid metabolism and cell activation. Accordingly, a subset of leukemia inhibitory factor–upregulated transcripts related to cholesterol metabolism and lipid internalization was validated by real-time quantitative polymerase chain reaction. This was accompanied by a leukemia inhibitory factor–enhanced capacity for lipid accumulation in macrophages upon incubation with oxidized low-density lipoprotein. Mechanistically, leukemia inhibitory factor triggered the phosphorylation (Y705 and S727) and nuclear translocation of the transcription factor STAT3 in bone marrow–derived macrophages. Consistent with this, ingenuity pathway analysis identified STAT3 as an upstream regulator of a subset of transcripts, including Il4ra, in leukemia inhibitory factor–treated macrophages. Notably, leukemia inhibitory factor priming enhanced bone marrow–derived macrophage responses to interleukin-4-mediated M2 polarization (i.e. increased arginase activity and accumulation of transcripts encoding for M2 markers). Conversely, leukemia inhibitory factor stimulation had no significant effect in bone marrow–derived macrophage responses to M1-polarizing stimuli (interferon-γ and lipopolysaccharide). Thus, our study provides insight into the transcriptional landscape of leukemia inhibitory factor–treated macrophages, shedding light on its role in lipid metabolism and M2 polarization responses. A better understanding of the regulatory mechanisms governing leukemia inhibitory factor–driven changes might help informing novel therapeutic approaches aiming to reprogram macrophage phenotypes in diseased states (e.g. cancer, atherosclerosis, and infection).