Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR.
Effective clearance of apoptotic cells by macrophages is essential for immune homeostasis. The transcriptional pathways that allow macrophages to sense and respond to apoptotic cells are poorly defined. We found that liver X receptor (LXR) signaling was important for both apoptotic cell clearance and the maintenance of immune tolerance. Apoptotic cell engulfment activated LXR and thereby induced the expression of Mer, a receptor tyrosine kinase critical for phagocytosis. LXR-deficient macrophages exhibited a selective defect in phagocytosis of apoptotic cells and an aberrant proinflammatory response to them. As a consequence of these defects, mice lacking LXRs manifested a breakdown in self-tolerance and developed autoantibodies and autoimmune glomerulonephritis. Treatment with an LXR agonist ameliorated disease progression in a mouse model of lupus-like autoimmunity. Thus, activation of LXR by apoptotic cells engages a virtuous cycle that promotes their own clearance and couples engulfment to the suppression of inflammatory pathways.
A-Gonzalez
Noelia
N
Immune Signaling Laboratory, Department of Biochemistry and Molecular Biology, School of Medicine, University of Las Palmas, ULPGC, 35016 Las Palmas, Spain.
Bensinger
Steven J
SJ
Hong
Cynthia
C
Beceiro
Susana
S
Bradley
Michelle N
MN
Zelcer
Noam
N
Deniz
Jose
J
Ramirez
Cristina
C
Díaz
Mercedes
M
Gallardo
German
G
de Galarreta
Carlos Ruiz
CR
Salazar
Jon
J
Lopez
Felix
F
Edwards
Peter
P
Parks
John
J
Andujar
Miguel
M
Tontonoz
Peter
P
Castrillo
Antonio
A
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015551:Autoimmunity / Q000276:immunology; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D000071518:Liver X Receptors; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D010587:Phagocytosis / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D000076202:c-Mer Tyrosine Kinase
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase