PMID- 30922944 OWN - NLM STAT- MEDLINE DCOM- 20191219 LR - 20191219 IS - 1879-355X (Electronic) IS - 0360-3016 (Linking) VI - 104 IP - 4 DP - 2019 Jul 15 TI - LXR Signaling Regulates Macrophage Survival and Inflammation in Response to Ionizing Radiation. PG - 913-923 LID - S0360-3016(19)30393-1 [pii] LID - 10.1016/j.ijrobp.2019.03.028 [doi] AB - 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 gamma-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 gamma-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-1beta, 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. CI - Copyright (c) 2019 Elsevier Inc. All rights reserved. FAU - Tabraue, Carlos AU - Tabraue C AD - Instituto Universitario de Investigaciones Biomedicas y Sanitarias (IUIBS) - Grupo de Investigacion Medio Ambiente y Salud (GIMAS) - Unidad de Biomedicina Asociada al Consejo Superior de Investigaciones Cientificas (Instituto de Investigaciones Biomedicas "Alberto Sols", CSIC), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain; Departamento de Morfologia, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. Electronic address: carlos.tabraue@ulpgc.es. FAU - Lara, Pedro C AU - Lara PC AD - Universidad Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain; Departamento de Oncologia, Hospital Universitario San Roque, Las Palmas de Gran Canaria, Spain. FAU - De Mirecki-Garrido, Mercedes AU - De Mirecki-Garrido M AD - Instituto Universitario de Investigaciones Biomedicas y Sanitarias (IUIBS) - Farmacologia Molecular y Traslacional - Departamento de Ciencias Clinicas, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. FAU - De La Rosa, Juan Vladimir AU - De La Rosa JV AD - Instituto Universitario de Investigaciones Biomedicas y Sanitarias (IUIBS) - Grupo de Investigacion Medio Ambiente y Salud (GIMAS) - Unidad de Biomedicina Asociada al Consejo Superior de Investigaciones Cientificas (Instituto de Investigaciones Biomedicas "Alberto Sols", CSIC), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. FAU - Lopez-Blanco, Felix AU - Lopez-Blanco F AD - Instituto Universitario de Investigaciones Biomedicas y Sanitarias (IUIBS) - Grupo de Investigacion Medio Ambiente y Salud (GIMAS) - Unidad de Biomedicina Asociada al Consejo Superior de Investigaciones Cientificas (Instituto de Investigaciones Biomedicas "Alberto Sols", CSIC), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. FAU - Fernandez-Perez, Leandro AU - Fernandez-Perez L AD - Instituto Universitario de Investigaciones Biomedicas y Sanitarias (IUIBS) - Farmacologia Molecular y Traslacional - Departamento de Ciencias Clinicas, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. FAU - Bosca, Lisardo AU - Bosca L AD - Instituto Universitario de Investigaciones Biomedicas y Sanitarias (IUIBS) - Grupo de Investigacion Medio Ambiente y Salud (GIMAS) - Unidad de Biomedicina Asociada al Consejo Superior de Investigaciones Cientificas (Instituto de Investigaciones Biomedicas "Alberto Sols", CSIC), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. FAU - Castrillo, Antonio AU - Castrillo A AD - Instituto Universitario de Investigaciones Biomedicas y Sanitarias (IUIBS) - Grupo de Investigacion Medio Ambiente y Salud (GIMAS) - Unidad de Biomedicina Asociada al Consejo Superior de Investigaciones Cientificas (Instituto de Investigaciones Biomedicas "Alberto Sols", CSIC), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190325 PL - United States TA - Int J Radiat Oncol Biol Phys JT - International journal of radiation oncology, biology, physics JID - 7603616 RN - 0 (Histones) RN - 0 (Interleukin-1beta) RN - 0 (Interleukin-6) RN - 0 (Liver X Receptors) RN - 0 (Trp53 protein, mouse) RN - 0 (Tumor Suppressor Protein p53) RN - 0 (gamma-H2AX protein, mouse) RN - 0 (interleukin-6, mouse) RN - EC 1.1.1.27 (L-Lactate Dehydrogenase) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) SB - IM MH - Animals MH - Cell Death MH - Cell Polarity MH - Cell Proliferation MH - *Cell Survival MH - DNA Breaks, Double-Stranded MH - Gamma Rays MH - Gene Expression MH - Histones/metabolism MH - Inflammation MH - Interleukin-1beta/metabolism MH - Interleukin-6/metabolism MH - L-Lactate Dehydrogenase/metabolism MH - Liver X Receptors/antagonists & inhibitors/genetics/*metabolism MH - Macrophages/drug effects/physiology/*radiation effects MH - Mice MH - Neoplasms/radiotherapy MH - Nitric Oxide Synthase Type II/metabolism MH - Pyroptosis MH - *Radiation Tolerance MH - Radiation, Ionizing MH - Reproducibility of Results MH - Tumor Suppressor Protein p53/metabolism EDAT- 2019/03/30 06:00 MHDA- 2019/12/20 06:00 CRDT- 2019/03/30 06:00 PHST- 2018/10/18 00:00 [received] PHST- 2019/02/19 00:00 [revised] PHST- 2019/03/17 00:00 [accepted] PHST- 2019/03/30 06:00 [pubmed] PHST- 2019/12/20 06:00 [medline] PHST- 2019/03/30 06:00 [entrez] AID - S0360-3016(19)30393-1 [pii] AID - 10.1016/j.ijrobp.2019.03.028 [doi] PST - ppublish SO - 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.