Figure 1. Innate immune mechanisms in SLE.

1A. An intact pathway for safe recognition and digestion of dead cells by macrophages includes a functional sensing mechanism, upregulation of scavenger receptors and activation of an alternative autophagy pathway called lysosome activated phagocytosis (LAP) that recruits part of the autophagy machinery, including LC3, to single membrane phagosomes and induces the release of regulatory cytokines such as IL-10 and TGFβ. Absence of LAP, but not of canonical autophagy in macrophages results in inefficient clearance of phagosomal material and release of inflammatory cytokines; this is associated with a mild spontaneous form of SLE in mouse models [58].

1B. Extracellular particles containing nucleic acids within immune complexes, microparticles, biofilms and neutrophil NETs are internalized, often via receptor mediated phagocytosis, and encounter endosomal Toll like receptors, TLRs 7, 8 and 9 within phagosomes. These TLRs use the adaptor molecular MyD88 and induce either inflammatory cytokines or Type 1 interferons. Absence of MyD88, IRAK4 and IRF5 all prevent SLE in mouse models. A role for DNAse1L3 in clearance of DNA associated with extracellular microparticles has recently been described [59].

1C. Intracellular nucleic acids engage a different set of sensors. The intracellular DNAse Trex1 clears cytoplasmic DNA; complete deficiency causes an interferonopathy called Aicardi-Goutieres syndrome. Cyclic GMP-AMP synthase (cGAS) catabolizes the formation of the cyclic dinucleotide cGAMP from excess digested cytoplasmic DNA. cGAMP binds to and activates the stimulator of IFN genes (STING), located in the endoplasmic reticulum, resulting in phosphorylation of NFκB and IRFs and the production of inflammatory cytokines. Similarly, cytoplasmic RNA sensors, RIG-I and MDA5 bind to MAVS, a mitochondrial membrane protein that similarly phosphorylates NFκB and IRFs to induce inflammatory cytokines needed for the anti-viral response. An immunogenic role has been defined for oxidized mitochondrial DNA released from activated neutrophils that do not perform mitophagy efficiently. Both TLR9 and STING have been implicated in recognition of neutrophil derived oxidized mitochondrial DNA [15,16]. Mitochondrial DNA released into the cytoplasm during apoptosis may also trigger the activation of cGAS.