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Int J Radiat Oncol Biol Phys. 2019 Jul 15;104(4):913-923. doi: 10.1016/j.ijrobp.2019.03.028. Epub 2019 Mar 25.

LXR Signaling Regulates Macrophage Survival and Inflammation in Response to Ionizing Radiation.

Author information

1
Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS) - Grupo de Investigación Medio Ambiente y Salud (GIMAS) - Unidad de Biomedicina Asociada al Consejo Superior de Investigaciones Científicas (Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain; Departamento de Morfología, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. Electronic address: carlos.tabraue@ulpgc.es.
2
Universidad Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain; Departamento de Oncología, Hospital Universitario San Roque, Las Palmas de Gran Canaria, Spain.
3
Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS) - Farmacología Molecular y Traslacional - Departamento de Ciencias Clínicas, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
4
Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS) - Grupo de Investigación Medio Ambiente y Salud (GIMAS) - Unidad de Biomedicina Asociada al Consejo Superior de Investigaciones Científicas (Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.

Abstract

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.

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