LXR-dependent gene expression is important for macrophage survival and the innate immune response

Cell. 2004 Oct 15;119(2):299-309. doi: 10.1016/j.cell.2004.09.032.


The liver X receptors (LXRs) are nuclear receptors with established roles in the regulation of lipid metabolism. We now show that LXR signaling not only regulates macrophage cholesterol metabolism but also impacts antimicrobial responses. Mice lacking LXRs are highly susceptible to infection with the intracellular bacteria Listeria monocytogenes (LM). Bone marrow transplant studies point to altered macrophage function as the major determinant of susceptibility. LXR-null macrophages undergo accelerated apoptosis when challenged with LM and exhibit defective bacterial clearance in vivo. These defects result, at least in part, from loss of regulation of the antiapoptotic factor SPalpha, a direct target for regulation by LXRalpha. Expression of LXRalpha or SPalpha in macrophages inhibits apoptosis in the setting of LM infection. Our results demonstrate that LXR-dependent gene expression plays an unexpected role in innate immunity and suggest that common nuclear receptor pathways mediate macrophage responses to modified lipoproteins and intracellular pathogens.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bone Marrow Transplantation
  • Cell Survival
  • Cells, Cultured
  • Cholesterol / metabolism*
  • DNA-Binding Proteins
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Immunity, Innate / physiology*
  • Listeria monocytogenes / metabolism
  • Listeriosis / metabolism
  • Liver X Receptors
  • Macrophages / cytology
  • Macrophages / immunology*
  • Macrophages / microbiology
  • Macrophages / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oligonucleotide Array Sequence Analysis
  • Orphan Nuclear Receptors
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism
  • Signal Transduction / physiology*
  • Survival Rate


  • DNA-Binding Proteins
  • Liver X Receptors
  • Nr1h3 protein, mouse
  • Orphan Nuclear Receptors
  • Protein Isoforms
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Immunologic
  • SPalpha protein, mouse
  • Cholesterol