The nuclear receptor LXRα controls the functional specialization of splenic macrophages.

Macrophages are professional phagocytic cells that orchestrate innate immune responses and have considerable phenotypic diversity at different anatomical locations. However, the mechanisms that control the heterogeneity of tissue macrophages are not well characterized. Here we found that the nuclear receptor LXRα was essential for the differentiation of macrophages in the marginal zone (MZ) of the spleen. LXR-deficient mice were defective in the generation of MZ and metallophilic macrophages, which resulted in abnormal responses to blood-borne antigens. Myeloid-specific expression of LXRα or adoptive transfer of wild-type monocytes restored the MZ microenvironment in LXRα-deficient mice. Our results demonstrate that signaling via LXRα in myeloid cells is crucial for the generation of splenic MZ macrophages and identify an unprecedented role for a nuclear receptor in the generation of specialized macrophage subsets

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

© 2021 Ramírez, Torrecilla-Parra, Pardo-Marqués, de-Frutos, Pérez-García, Tabraue, de la Rosa, Martín-Rodriguez, Díaz-Sarmiento, Nuñez, Orizaola, Través, Camps, Boscá and Castrillo.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.We thank MINECO FPI predoctoral fellowship granted to MCO (BES-2015-075339). Experimental work was supported by grants from Ministerio de Ciencia, Investigación y Universidades, y Fondo Europeo de Desarrollo Regional (FEDER) Grant REF: PID2019-104284RB-I00/AEI/10.13039/501100011033 (to AC) and support from Networks of Excellence from MINECO (Nuclear Receptors in Cancer, Metabolism and Inflammation [NuRCaMeIn] SAF2017-90604-REDT to AC. Ministerio de Economía, Industria y Competitividad, Ministerio de Ciencia, Investigación y Universidades, and Agencia Estatal de Investigación (SAF2017-82436-R, RTC2017-6283-1), Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CB16/11/00222), Consorcio de Investigación en Red de la Comunidad de Madrid, S2017/BMD-3686 and Fondo Europeo de Desarrollo Regional (to LB). Ministerio de Ciencia, Investigación y Universidades, and Agencia Estatal de Investigación Proyectos de I+D+i Retos Investigación 2018 (RTI2018-095061-B-I00); TALENTO Grant from Madrid Government, Spain (2017-T1/BMD-5333); Consejería de Ciencia, Universidades e Innovación Comunidad de Madrid, Spain (PEJD-2018-POST/BMD-8900 and PEDJ-2018-AI/BDM-9724) to CMR

LXR signaling regulates macrophage survival and inflammation in response to ionizing radiation

[Purpose]: To evaluate the role of liver X receptor (LXR) nuclear receptors on irradiation-induced cell death and polarization of macrophages and the potential implications in the context of radiation therapy treatment of cancer.[Methods and Materials]: Primary and immortalized murine bone marrow–derived macrophages (BMDMs) from wild type or LXR double knock-out mice were exposed to gamma irradiation. Subsequently, analysis of LXR signaling on cell proliferation and cytotoxicity induced by ionizing radiation was determined by time-lapse photomicroscopy. Genotoxic cell damage was evaluated by Western blot of γ-H2AX and p53. Pyroptosis was analyzed through cell viability assay, lactate dehydrogenase release assay, and Western blot of caspase-1 active protein. Expression of inflammatory markers was measured by real-time quantitative polymerase chain reaction.[Results]: Genetic and pharmacologic inactivation of LXR induced radiosensitivity of macrophages. LXR deficiency decreased cell proliferation and enhanced cytotoxicity induced by ionizing radiation in both immortalized and primary BMDMs. Protein levels of γ-H2AX and p53, both involved in response to cell damage, were exacerbated in LXR-deficient macrophages exposed to irradiation. Cell membrane damage was augmented and cell viability was decreased in LXR-deficient macrophages compared with LXR wild type macrophages in response to irradiation. In addition, LXR deficiency enhanced both caspase-1 activation and lactate dehydrogenase release in BMDM exposed inflammasome activators. LXR inactivation or deficiency markedly increased the expression of proinflammatory markers IL-1β, IL-6, and inducible nitric oxide synthase in irradiated macrophages.[Conclusions]: The present work identifies LXR transcription factors as potential therapeutic targets to enhance the suppressive effects of radiation therapy on tumor growth through induction of macrophage cell death and activation of the inflammatory cascade.This work was supported by grants SAF2014-56819-R, SAF2017-82436R and S2017-BMD-8636 from MINECO (Spain); Grant for Networks of Excellence from MINECO (Spain) “Nuclear Receptors in Cancer, Metabolism and Inflammation” (NuRCaMeIn) SAF2015-71878-REDT and SAF2017-90604-REDT.Peer reviewe

The nuclear receptor LXRα controls the functional specialization of splenic macrophages.

Macrophages are professional phagocytic cells that orchestrate innate immune responses and have considerable phenotypic diversity at different anatomical locations. However, the mechanisms that control the heterogeneity of tissue macrophages are not well characterized. Here we found that the nuclear receptor LXRα was essential for the differentiation of macrophages in the marginal zone (MZ) of the spleen. LXR-deficient mice were defective in the generation of MZ and metallophilic macrophages, which resulted in abnormal responses to blood-borne antigens. Myeloid-specific expression of LXRα or adoptive transfer of wild-type monocytes restored the MZ microenvironment in LXRα-deficient mice. Our results demonstrate that signaling via LXRα in myeloid cells is crucial for the generation of splenic MZ macrophages and identify an unprecedented role for a nuclear receptor in the generation of specialized macrophage subsets

Anales de Edafología y Agrobiología Tomo 47 Número 7-8

l. Suelos. Química. Estudio de los suelos de la depresión Guadix-Baza (Granada). II. Análisis de factores en modo R. Por A. lriarte Mayo, A . Pozzuoli y E. Barahona Fernández. Revisión del método de determinación automatizada de nitrógeno U. V. oxidable en extractos de suelos. Por J. A. Díez.-- Biología Consideraciones ecológicas y bioquímicas sobre la humificación en sabinares desarrollados sobre material calizo y gneísico. Por M. R. Rodríguez y F. Velasco.-- Génesis, Clasificación y Cartografía Suelos, geología y geomorfología en zonas erosionadas de la cuenca del Valdeamargos, depresión de Calatayud. Por M. A. Mulders, J. Slurink y J. Boixadera.-- Aplicación de la metodología de la cartografía básica a la comarca La Plana de Requena-Utiel (Valencia). Por R. Boluda Hernández, M. Moraleda Esteve, V. Andréu Pérez y J. Sánchez Díaz.-- Estudio de caracterización de minerales (fracción arena) en suelos gleicos de una zona semiárida. Por Mª P. García Rodríguez, J. Fortéza Bonnin, A. García Rodríguez y L. F. Lorenzo Martín, con la colaboración técnica de N. Najac Ballesteros.-- Clasificación de sectores ecológicos en la sierra del Negrete y Utiel (Valencia), utilizando el sensor thematic mapper del satélite Landsat-5. Por R. Boluda Hernández.-- Unidades de paisaje en el tercio norte del valle de Ayora (Valencia, España). Por J. A. Hernandez y J. L. Rubio.-- Suelos de la Isla de Gomera (1. Canarias). l. Vertiente septentrional. Características morfológicas, físico-químicas, mineralógicas, micromorfológicas, clasificación e interpretación. Por C. Jiménez Mendoza, M. L. Tejedor Salguero y A. Rodríguez Rodríguez.-- Suelos de la Isla de Gomera (1. Canarias). 11. Vertiente meridfonal. Ecología, Características morfológicas, físico-químicas, mineralógicas. micromorfológicas, clasificación e interpretación. Por C. Jiménez Mendoza, A. Rodrr'guez Rodríguez y M. L. Tejedor Salguero.--. Fertilidad Efecto de fertilizantes orgánicos sobre el cultivo de patatas y sobre las propiedades del suelo. Por J. A. Haroun Tabraue y E. Hernández.-- II. Biología Vegetal-Nutrición. Influencia del sistema de nutrición en la calidad de los frutos de tomate. l. Rendimientos, parámetros físicos, fracciones nitrogenadas, acidez y azúcares. Por F.J. López-Andréu, R . M. Esteban, E. Molla y O. Carpena.-- Influencia del sistema de nutrición en la calidad de los frutos de tomate. 11. Caro- tenoides, ácido ascórbico, sustancias pécticas y Flavonoides. Por F. J. López- Andréu, R. M. Esteban, E. Molla y O. Carpena.-- Fisiología Efecto de tres cultivares en el vigor de semillas de girasol. Por M. Torres y C. J. Martínez-Honduvilla.-- Agro biología Effect of qualities of irrigation water and N P K fertilizers on soil properties. Por P. Lal and R. Lal.-- Modelos estructurales condicionados por el arbolado en comunidades de diferente trofismo. Por A. Puerto, J. A. Garcra, M. D. Matías, J. A. Saldaña y C. Pérez.-- III. Trabajo recapitulativo. Relación entre el contenido de¡olifenoles y actividad fotosintéticas bajo radiación ultravioleta. PorJ. Baztan y RuanoPeer reviewe

The nuclear receptor LXRα controls the functional specialization of splenic macrophages

Macrophages are professional phagocytic cells that orchestrate innate immune responses and display remarkable phenotypic diversity at different anatomical locations. However, the mechanisms that control the heterogeneity of tissue macrophages are not well characterized. Here, we report that the nuclear receptor LXRα is essential for the differentiation of macrophages in the marginal zone (MZ) of the spleen. LXR deficient mice are defective in the generation of MZ and metallophilic macrophages, resulting in abnormal responses to blood-borne antigens. Myeloid specific expression of LXRα or adoptive transfer of wild-type monocytes rescues the MZ microenvironment in LXRα deficient mice. These results demonstrate that LXRα signaling in myeloid cells is crucial for the generation of splenic MZ macrophages and reveal an unprecedented role for a nuclear receptor in the generation of specialized macrophage subsets