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

Ramírez, Cristina M., Torrecilla-Parra, Marta, Pardo-Marqués, Virginia, de-Frutos, Mario Fernández, Pérez-García, Ana, Tabraue, Carlos, de la Rosa, Juan Vladimir, Martín-Rodriguez, Patricia, Díaz-Sarmiento, Mercedes, Nuñez, Uxue, Orizaola, Marta C., Través, Paqui G., Camps, Marta, Boscá, Lisardo, Castrillo, Antonio·2021·Frontiers in Endocrinology
DOI 10.3389/fendo.2021.635923
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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.

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  • Elevated cholesterol promotes a pro-inflammatory M1 macrophage phenotype.

    “elevated cholesterol promotes a pro-inflammatory M1 phenotype22–25”

    From Macrophage INSIG1 deficiency drives psoriasiform dermatitis via the SREBP2-STAT1 axis (2026) · cites this paper as [24]

    The Introduction (page unavailable) says cholesterol accumulation activates LXR and promotes cholesterol efflux, while LXR activation can repress inflammatory genes. The cited paper links cholesterol regulation and inflammation, but the passages found do not say that elevated cholesterol promotes an M1 phenotype. Searches for M1 polarization and cholesterol-induced inflammatory signaling did not establish that claim. (LLM, conf=0.73)

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Research works printed but not linked: 56

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Metadata

Authors
Ramírez, C. M., Torrecilla-Parra, M., Pardo-Marqués, V., de-Frutos, M. F., Pérez-García, A., Tabraue, C., de la Rosa, J. V., Martín-Rodriguez, P., Díaz-Sarmiento, M., Nuñez, U., Orizaola, M. C., Través, P. G., Camps, M., Boscá, L., & Castrillo, A.
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2021-05-27
Volume
12
ISSN
1664-2392
DOI
10.3389/fendo.2021.635923
Cited by
34
References
8
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Ministerio de Economía, Industria y Competitividad, Gobierno de España (SAF2017-82436-R, RTC2017-6283-1)
  • Ministerio de Ciencia, Innovación y Universidades (PID2019-104284RB-I00/AEI/10.13039/501100011033, RTI2018-095061-B-I00, PID2019-104284RB-I00/AEI/10.13039/501100011033)

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