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Immunity. 2012 Dec 14;37(6):986-997. doi: 10.1016/j.immuni.2012.09.014. Epub 2012 Dec 6.

Noncanonical autophagy is required for type I interferon secretion in response to DNA-immune complexes.

Author information

1
Respiratory, Inflammation and Autoimmunity Research Department, Gaithersburg, MD 20878, USA.
2
Department Immunology, St. Jude Children's Research Institute, Memphis, TN 38105, USA.
3
Department of Antibody Discovery and Protein Engineering MedImmune, Gaithersburg, MD 20878, USA.
4
Department of Immunology, Yale University School of Medicine, New Haven, CT 06520, USA.
5
Institute of Innate Immunity, Biomedical Center, 1G008, University Hospitals, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
6
Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
#
Contributed equally

Abstract

Toll-like receptor-9 (TLR9) is largely responsible for discriminating self from pathogenic DNA. However, association of host DNA with autoantibodies activates TLR9, inducing the pathogenic secretion of type I interferons (IFNs) from plasmacytoid dendritic cells (pDCs). Here, we found that in response to DNA-containing immune complexes (DNA-IC), but not to soluble ligands, IFN-α production depended upon the convergence of the phagocytic and autophagic pathways, a process called microtubule-associated protein 1A/1B-light chain 3 (LC3)-associated phagocytosis (LAP). LAP was required for TLR9 trafficking into a specialized interferon signaling compartment by a mechanism that involved autophagy-related proteins, but not the conventional autophagic preinitiation complex, or adaptor protein-3 (AP-3). Our findings unveil a new role for nonconventional autophagy in inflammation and provide one mechanism by which anti-DNA autoantibodies, such as those found in several autoimmune disorders, bypass the controls that normally restrict the apportionment of pathogenic DNA and TLR9 to the interferon signaling compartment.

PMID:
23219390
PMCID:
PMC3786711
DOI:
10.1016/j.immuni.2012.09.014
[Indexed for MEDLINE]
Free PMC Article

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