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Liver X receptor-dependent repression of matrix metalloproteinase-9 expression in macrophages
Antonio Castrillo1, Sean B Joseph, Chaitra Marathe
1Howard Hughes Medical Institute, University of California, Los Angeles 90095, USA.
Abstract:
Matrix metalloproteinases (MMPs) are zinc endopeptidases that degrade extracellular matrix (ECM) components during normal and pathogenic tissue remodeling. Inappropriate expression of these enzymes contributes to the development of vascular pathology, including atherosclerosis. MMP-9 is expressed in its active form in atherosclerotic lesions and is believed to play an important role in vascular remodeling, smooth muscle cell migration, and plaque instability. We demonstrate here that the liver X receptors (LXRs) LXRalpha and LXRbeta inhibit basal and cytokine-inducible expression of MMP-9. Treatment of murine peritoneal macrophages with the synthetic LXR agonists GW3965 or T1317 reduces MMP-9 mRNA expression and blunts its induction by pro-inflammatory stimuli including lipopolysaccharide, interleukin-1beta, and tumor necrosis factor alpha. In contrast, macrophage expression of MMP-12 and MMP-13 is not altered by LXR ligands. We further show that the ability of LXR ligands to regulate MMP-9 expression is strictly receptor-dependent and is not observed in macrophages obtained from LXRalphabeta null mice. Analysis of the 5'-flanking region of the MMP-9 gene indicates that LXR/RXR heterodimers do not bind directly to the MMP-9 promoter. Rather, activation of LXRs represses MMP-9 expression, at least in part through antagonism of the NFkappaB signaling pathway. These observations identify the regulation of macrophage MMP-9 expression as a mechanism whereby activation of LXRs may impact macrophage inflammatory responses.
Insights
Liver X receptors (LXRs) suppress matrix metalloproteinase-9 (MMP-9) expression in macrophages. LXR activation inhibits MMP-9, potentially impacting inflammatory responses in vascular diseases like atherosclerosis.
Area of Science:
- Molecular biology
- Immunology
- Cardiovascular research
Background:
- Matrix metalloproteinases (MMPs), particularly MMP-9, are implicated in vascular pathology, including atherosclerosis, due to their role in extracellular matrix degradation and plaque instability.
- Dysregulated MMP expression contributes to pathological tissue remodeling and disease progression.
Purpose of the Study:
- To investigate the role of liver X receptors (LXRs) in regulating matrix metalloproteinase-9 (MMP-9) expression in macrophages.
- To elucidate the mechanism by which LXRs influence MMP-9 expression and its potential impact on inflammatory responses.
Main Methods:
- Murine peritoneal macrophages were treated with synthetic LXR agonists (GW3965, T1317).
- MMP-9 mRNA expression was analyzed using quantitative PCR.
- Macrophage responses to pro-inflammatory stimuli (LPS, IL-1β, TNFα) were assessed with and without LXR activation.
- Experiments were conducted using wild-type and LXRαβ null macrophages.
- Analysis of the MMP-9 gene promoter and NFκB signaling pathway was performed.
Main Results:
- LXR agonists significantly reduced basal and cytokine-inducible MMP-9 mRNA expression in macrophages.
- LXR activation did not affect MMP-12 or MMP-13 expression.
- The inhibitory effect of LXR ligands on MMP-9 was dependent on LXRα and LXRβ expression.
- LXR/RXR heterodimers did not directly bind to the MMP-9 promoter.
- LXR activation repressed MMP-9 expression, partly by antagonizing the NFκB signaling pathway.
Conclusions:
- Liver X receptors (LXRs) inhibit both basal and induced expression of MMP-9 in macrophages.
- LXR-mediated repression of MMP-9 occurs independently of direct promoter binding and involves antagonism of the NFκB pathway.
- Regulation of macrophage MMP-9 expression by LXRs represents a novel mechanism influencing inflammatory responses in the context of vascular diseases.