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IL-36/LXR axis modulates cholesterol metabolism and immune defense to Mycobacterium tuberculosis

ABSTRACT: Mycobacterium tuberculosis (Mtb) is a life-threatening pathogen in humans. Bacterial infection of macrophages usually triggers strong innate immune mechanisms, including IL-1 cytokine secretion. The newer member of the IL-1 family, IL-36, was recently shown to be involved in cellular defense against Mtb. To unveil the underlying mechanism of IL-36 induced antibacterial activity, we analyzed its role in the regulation of cholesterol metabolism, together with the involvement of Liver X Receptor (LXR) in this process. Here we report that, in Mtb-infected macrophages, IL-36 signaling modulates cholesterol biosynthesis and efflux via LXR. Moreover, IL-36 induces the expression of cholesterol-converting enzymes and the accumulation of LXR ligands, such as oxysterols. Ultimately, both IL-36 and LXR signaling play a role in the regulation of antimicrobial peptides expression and in Mtb growth restriction. These data provide novel evidence for the importance of IL‑36 and cholesterol metabolism mediated by LXR in cellular host defense against Mtb.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103092 | GEO | 2018/02/14

REPOSITORIES: GEO

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Project description:The objective of the study was to figure out the impact of LXR signaling on human macrophages. Primary human macrophages in an early differentiating and a mature differentiation state were treated with the LXR agonist T091317 for 4 and 24 h and transcriptome-wide expression analysis were performed. As LXRa is highly induced during macrophage differentiation and 68% of all LXRs targets change their expression during this process, we suggest that LXRs have essential functions in macrophage development. More than 238 genes are regulated in early as well as mature macrophages by activation of LXRs; most of them are up-regulated. LXRs administrate differentiation state specific as well as common macrophages functions related primarily to lipid homeostasis, immune response and cell fate. Interestingly, almost only genes related to lipid and cholesterol metabolism are overrepresented among early induced genes, whereas genes related to immune functions respond later, implying the existence of indirect mechanisms of control. Furthermore, in early differentiating macrophages cell proliferation and cell death associated genes are induced after 24 h of LXR activation, whereas in mature macrophages, showing high LXRa expression, the same functional cluster respond far earlier (4 h) after LXR ligand treatment. In conclusion, our data suggest that LXRs are modulators of macrophage differentiation, operating principally as positive transcriptional regulators of genes involved in lipid and cholesterol metabolism and by this indirectly influencing the immunophenotype of macrophages. CD14 positive cells of healthy donors were isolated by magnetic separation and differentiated in the presence of human serum to macrophages. At an early differentiating state (16 h after isolation) and at in mature differentiating state (day 11 after isolation) the cells were treated with the synthetical LXR agonist T091317 respective its solvent DMSO for 4 and 24 h. RNA was isolated and a whole genome microarray was performed.

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IL-36/LXR axis modulates cholesterol metabolism and immune defense to Mycobacterium tuberculosis

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