Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells.
Defects in clearance of dying cells have been proposed to underlie the pathogenesis of systemic lupus erythematosus (SLE). Mice lacking molecules associated with dying cell clearance develop SLE-like disease, and phagocytes from patients with SLE often display defective clearance and increased inflammatory cytokine production when exposed to dying cells in vitro. Previously, we and others described a form of noncanonical autophagy known as LC3-associated phagocytosis (LAP), in which phagosomes containing engulfed particles, including dying cells, recruit elements of the autophagy pathway to facilitate maturation of phagosomes and digestion of their contents. Genome-wide association studies have identified polymorphisms in the Atg5 (ref. 8) and possibly Atg7 (ref. 9) genes, involved in both canonical autophagy and LAP, as markers of a predisposition for SLE. Here we describe the consequences of defective LAP in vivo. Mice lacking any of several components of the LAP pathway show increased serum levels of inflammatory cytokines and autoantibodies, glomerular immune complex deposition, and evidence of kidney damage. When dying cells are injected into LAP-deficient mice, they are engulfed but not efficiently degraded and trigger acute elevation of pro-inflammatory cytokines but not anti-inflammatory interleukin (IL)-10. Repeated injection of dying cells into LAP-deficient, but not LAP-sufficient, mice accelerated the development of SLE-like disease, including increased serum levels of autoantibodies. By contrast, mice deficient in genes required for canonical autophagy but not LAP do not display defective dying cell clearance, inflammatory cytokine production, or SLE-like disease, and, like wild-type mice, produce IL-10 in response to dying cells. Therefore, defects in LAP, rather than canonical autophagy, can cause SLE-like phenomena, and may contribute to the pathogenesis of SLE.
Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.|Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, Research Triangle Park, North Carolina 27709, USA.
Jennifer
J
Martinez
Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Larissa D
LD
Cunha
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Sunmin
S
Park
Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Mao
M
Yang
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Qun
Q
Lu
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Robert
R
Orchard
University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Quan-Zhen
QZ
Li
University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Mei
M
Yan
Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Laura
L
Janke
Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Cliff
C
Guy
Division of Nephrology and Hypertension, Christian-Albrechts-University, Kiel 24105, Germany.
Andreas
A
Linkermann
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Herbert W
HW
Virgin
Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Douglas R
DR
Green
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood; D001343:Autophagy / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000473:pathology*; D016753:Interleukin-10 / Q000096:biosynthesis; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010586:Phagocytes / Q000166:cytology / Q000502:physiology; D010588:Phagosomes / Q000502:physiology
D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D016207:Cytokines; D008869:Microtubule-Associated Proteins; D016753:Interleukin-10