LC3-associated phagocytosis mediates IFN-alpha secretion in response to DNA-immune complexes. (BA3P.207)

TLR9 compartmentalization is largely responsible for discriminating self from pathogenic DNA. However, association of host DNA with autoantibodies activates TLR9, inducing the secretion of large amounts of type I IFNs in plasmacytoid dendritic cells. Here, we show that TLR9-mediated production of IFN-α depends on the convergence of the phagocytic and autophagic pathways in response to DNA-containing immune complexes, a process called LC3-associated phagocytosis (LAP). LAP is required for TLR9 trafficking into a specialized IRF7-signaling compartment (ISC) by a mechanism that involves ATG7 but not the conventional autophagic pre-initiation complex. Progression to this compartment did not require AP-3, a protein that mediates TLR9 trafficking and IFN-α secretion in response to CpG oligonucleotides. Our findings unveil a new role for autophagy in inflammatory responses, and provide one of the mechanisms by which anti-DNA autoantibodies, such as those found in several autoimmune disorders, bypass the controls that normally restrict TLR9 activation to pathogenic DNA. Further, we have established phagosomal enrichment assays that will allow us to characterize precise nature ISC as well as the role of LAP in ISC regulation .