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RETRACTED ARTICLE: Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells
Open accessAbstract
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.
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“Rubicon has been shown to be an inhibitor of canonical autophagy (Matsunaga et al., 2009) and a key component of a non-canonical function of autophagy proteins that modulates inflammatory immune activation (Cunha et al., 2018; Martinez et al., 2016).”
From LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease (2019) · cites this paper as Martinez et al., 2016
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“Since we have previously shown a vital role for LAP in regulating inflammatory immune responses (Martinez et al., 2016), we hypothesized that defective LANDO may have a similar effect.”
From LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease (2019) · cites this paper as Martinez et al., 2016
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Metadata
- Authors
- Martinez, J., Cunha, L. D., Park, S., Yang, M., Lu, Q., Orchard, R., Li, Q.-Z., Yan, M., Janke, L., Guy, C., Linkermann, A., Virgin, H. W., & Green, D. R.
- Affiliations
- National Institutes of Health (US)
- St. Jude Children's Research Hospital (US)
- Washington University in St. Louis (US)
- The University of Texas Southwestern Medical Center (US)
- Christian-Albrechts-Universität zu Kiel (DE)
- Corresponding author
- Martinez, Jennifer
- Green, Douglas R.
- ORCID
- Venue
- Nature
- Published
- 2016-04-20
- Volume
- 533
- Issue
- 7601
- Pages
- 115-119
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4860026
- OpenAlex
- W2338725336
- Cited by
- 381
- References
- 31
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 17 · 2023: 21 · 2022: 52 · 2021: 57 · 2020: 41 · 2019: 52 · 2018: 50 · 2017: 52 · 2016: 31
- FWCI
- 65.62
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (1ZIAES10328601)
- National Cancer Institute (P30CA021765)
- National Institute of Allergy and Infectious Diseases (R01AI040646, R01AI40646, U19AI109725, T32AI007163)
- National Institute of Environmental Health Sciences (ZIAES103286)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- LC3-associated phagocytosis, non-canonical autophagy, systemic lupus erythematosus, autoinflammation, autoantibodies, anti-DNA antibodies, phagosome maturation, ATG5, ATG7, kidney disease, inflammatory cytokines, autoimmunity, retracted article
- MeSH terms
- Animals, Antigen-Antibody Complex, Autoantibodies, Autophagy, Inflammation, Kidney, Lupus Erythematosus, Systemic, Male, Microtubule-Associated Proteins, Phagocytes, Phagosomes, Cytokines, Interleukin-10, Mice
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