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

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.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death
  • Cell Polarity
  • Cell Proliferation
  • Cell Survival*
  • DNA Breaks, Double-Stranded
  • Gamma Rays
  • Gene Expression
  • Histones / metabolism
  • Inflammation
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism
  • L-Lactate Dehydrogenase / metabolism
  • Liver X Receptors / antagonists & inhibitors
  • Liver X Receptors / genetics
  • Liver X Receptors / metabolism*
  • Macrophages / drug effects
  • Macrophages / physiology
  • Macrophages / radiation effects*
  • Mice
  • Neoplasms / radiotherapy
  • Nitric Oxide Synthase Type II / metabolism
  • Pyroptosis
  • Radiation Tolerance*
  • Radiation, Ionizing
  • Reproducibility of Results
  • Tumor Suppressor Protein p53 / metabolism


  • Histones
  • Interleukin-1beta
  • Interleukin-6
  • Liver X Receptors
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • gamma-H2AX protein, mouse
  • interleukin-6, mouse
  • L-Lactate Dehydrogenase
  • Nitric Oxide Synthase Type II