Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus

Activation of innate sensors by self-antigen contributes to autoimmunity, although how intracellular sensors are chronically exposed to self-antigen has remained unknown. Here, we identify a previously unidentified defect in which lupus-prone macrophages fail to mature the lysosome, promoting the accumulation of apoptotic debris-containing IgG-immune complexes (IgG-ICs). Interestingly, macrophages from other autoimmune diseases accumulate IgG-ICs, indicating that lysosomal defects may underlie multiple autoimmune diseases. Furthermore, the prolonged intracellular residency chronically activates Toll-like receptors and permeabilizes the phagolysosomal membrane, allowing activation of cytosolic sensors. These findings identify lysosomal maturation as a unique defect in MRL/lpr mice that impacts multiple events known to underlie SLE, including pathogenic cytokine secretion.