Crosstalk Between LXR and Caveolin-1 Signaling Supports Cholesterol Efflux and Anti-Inflammatory Pathways in Macrophages

Abstract

Macrophages are immune cells that play crucial roles in host defense against pathogens by triggering their exceptional phagocytic and inflammatory functions. Macrophages that reside in healthy tissues also accomplish important tasks to preserve organ homeostasis, including lipid uptake/efflux or apoptotic-cell clearance. Both homeostatic and inflammatory functions of macrophages require the precise stability of lipid-rich microdomains located at the cell membrane for the initiation of downstream signaling cascades. Caveolin-1 (Cav-1) is the main protein responsible for the biogenesis of caveolae and plays an important role in vascular inflammation and atherosclerosis. The Liver X receptors (LXRs) are key transcription factors for cholesterol efflux and inflammatory gene responses in macrophages. Although the role of Cav-1 in cellular cholesterol homeostasis and vascular inflammation has been reported, the connection between LXR transcriptional activity and Cav-1 expression and function in macrophages has not been investigated. Here, using gain and loss of function approaches, we demonstrate that LXR-dependent transcriptional pathways modulate Cav-1 expression and compartmentation within the membrane during macrophage activation. As a result, Cav-1 participates in LXR-dependent cholesterol efflux and the control of inflammatory responses. Together, our data show modulation of the LXR-Cav-1 axis could be exploited to control exacerbated inflammation and cholesterol overload in the macrophage during the pathogenesis of lipid and immune disorders, such as atherosclerosis.

Role of miR-199a-5p in the post-transcriptional regulation of ABCA1 in response to hypoxia in peritoneal macrophages

“…Additionally, miR-199a-5p is highly expressed in aorta and cardiometabolic tissues and organs such as aorta, heart, lung in humans, where hypoxia is a critical triggering factor of many associated diseases, including atherosclerosis. In this sense, besides the targeting key cholesterol genes ABCA1 or ABCG1 shown here, some of our recent studies demonstrated that Cav-1 may influence ABCA1 functions ( 57 ). Cav-1 is traditionally considered a cholesterol-binding protein that is able to shuttle cholesterol between various cell membranes ( 58 ), and acts as a central regulator of cholesterol metabolism during atherosclerosis, which varies depending on the cell type involved.…”

“…Cav-1 is traditionally considered a cholesterol-binding protein that is able to shuttle cholesterol between various cell membranes ( 58 ), and acts as a central regulator of cholesterol metabolism during atherosclerosis, which varies depending on the cell type involved. For instance, Cav-1 absence in aortic endothelial inhibits atherosclerosis by attenuating LDL transcytosis and enhancing autophagic flux ( 59 , 60 ), while in macrophages Cav-1 promotes THP-1 differentiation, ABCA1 expression and cholesterol efflux ( 57 , 61 , 62 ). Indeed, Cav-1 participates in LXR-dependent anti-atherogenic functions including ABCA1 localization, cholesterol efflux as well as the control of inflammatory responses in macrophages ( 57 ).…”

“…For instance, Cav-1 absence in aortic endothelial inhibits atherosclerosis by attenuating LDL transcytosis and enhancing autophagic flux ( 59 , 60 ), while in macrophages Cav-1 promotes THP-1 differentiation, ABCA1 expression and cholesterol efflux ( 57 , 61 , 62 ). Indeed, Cav-1 participates in LXR-dependent anti-atherogenic functions including ABCA1 localization, cholesterol efflux as well as the control of inflammatory responses in macrophages ( 57 ). Interestingly, it has been reported a crosstalk between LXR and HIF-1α, the primary transcription factor involved in hypoxia and its implication in foam cell formation ( 63 , 64 ).…”

Novel insights into the regulation of cellular catabolic metabolism in macrophages through nuclear receptors

“…The NRs described herein are pivotal regulators of cellular catabolic metabolism in macrophages (see Table 1, where the known effects NRs specifically on cellular metabolism are listed). While PPARs regulate lipid and cholesterol metabolism, particularly in atherosclerosis, and were long recognised as modulators of myeloid cells and immunity, recent publications have revealed that also other NRs, previously only known to modulate immunity in macrophages through the regulation of cytokines and myeloid activation genes, can use cellular metabolism to achieve their immunoregulatory functions [70,92,113,121,122] (Table 1). Other transcription factors are intimately involved in cellular metabolism, the most prominent being HIF1a, which interacts with NRs, and is a major node in the control of myeloid metabolism by NR.…”

Metabolic regulation of immune responses to cancer

“…Regardless of the complicated roles of fatty acid β-oxidation in IL-4-driven M2 macrophage differentiation, unsaturated fatty acids such as oleate promote the immunosuppressive and pro-tumor phenotype of TAMs through lipid droplet-dependent mechanisms 83 . In addition, SREBP1-dependent production of anti-inflammatory fatty acids contributes to the resolution of TLR4-mediated inflammation 84 , and Caveolin-1 participates in LXR-dependent cholesterol efflux and mediates anti-inflammatory properties 85 . Similarly, ovarian cancer cells facilitate membrane cholesterol efflux in TAMs, thus resulting in lipid raft breakdown and a subsequent increase in IL-4 signaling, which fosters the immunosuppressive TAM phenotype 86 .…”