LXR-dependent gene expression is important for macrophage survival and the innate immune response.
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.
Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.
Sean B
SB
Joseph
Michelle N
MN
Bradley
Antonio
A
Castrillo
Kevin W
KW
Bruhn
Puiying A
PA
Mak
Liming
L
Pei
John
J
Hogenesch
Ryan M
RM
O'connell
Genhong
G
Cheng
Enrique
E
Saez
Jeffery F
JF
Miller
Peter
P
Tontonoz
D000818:Animals; D016026:Bone Marrow Transplantation; D002470:Cell Survival; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007113:Immunity, Innate / Q000502:physiology*; D008089:Listeria monocytogenes / Q000378:metabolism; D008088:Listeriosis / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000382:microbiology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015996:Survival Rate; D051017:Apoptosis Regulatory Proteins; D051116:Receptors, Scavenger
D002784:Cholesterol; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; C000605214:Nr1h3 protein, mouse; C117272:Cd5l protein, mouse; D051017:Apoptosis Regulatory Proteins; D051116:Receptors, Scavenger