Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells

Jennifer Martinez, Larissa D. Cunha, Sunmin Park, Mao Yang, Qun Lu, Robert Orchard, Quan Zhen Li, Mei Yan, Laura Janke, Cliff Guy, Andreas Linkermann, Herbert W. Virgin, Douglas R. Green

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)115-119
Number of pages5
JournalNature
Volume533
Issue number7601
DOIs
StatePublished - May 5 2016

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Autophagy
Phagocytosis
Systemic Lupus Erythematosus
Cytokines
Phagosomes
Interleukin-10
Autoantibodies
Genome-Wide Association Study
Phagocytes
Antigen-Antibody Complex
Serum
Genes
Digestion
Anti-Inflammatory Agents
Kidney
Injections

ASJC Scopus subject areas

  • General

Cite this

Martinez, J., Cunha, L. D., Park, S., Yang, M., Lu, Q., Orchard, R., ... Green, D. R. (2016). Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. Nature, 533(7601), 115-119. https://doi.org/10.1038/nature17950

Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. / Martinez, Jennifer; Cunha, Larissa D.; Park, Sunmin; Yang, Mao; Lu, Qun; Orchard, Robert; Li, Quan Zhen; Yan, Mei; Janke, Laura; Guy, Cliff; Linkermann, Andreas; Virgin, Herbert W.; Green, Douglas R.

In: Nature, Vol. 533, No. 7601, 05.05.2016, p. 115-119.

Research output: Contribution to journalArticle

Martinez, J, Cunha, LD, Park, S, Yang, M, Lu, Q, Orchard, R, Li, QZ, Yan, M, Janke, L, Guy, C, Linkermann, A, Virgin, HW & Green, DR 2016, 'Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells', Nature, vol. 533, no. 7601, pp. 115-119. https://doi.org/10.1038/nature17950
Martinez J, Cunha LD, Park S, Yang M, Lu Q, Orchard R et al. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. Nature. 2016 May 5;533(7601):115-119. https://doi.org/10.1038/nature17950
Martinez, Jennifer ; Cunha, Larissa D. ; Park, Sunmin ; Yang, Mao ; Lu, Qun ; Orchard, Robert ; Li, Quan Zhen ; Yan, Mei ; Janke, Laura ; Guy, Cliff ; Linkermann, Andreas ; Virgin, Herbert W. ; Green, Douglas R. / Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. In: Nature. 2016 ; Vol. 533, No. 7601. pp. 115-119.
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AB - 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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