Defects in the clearance of dying cells have been implicated in the process of SLE. We have identified a novel process, LC3-associated phagocytosis (LAP), in which components of the canonical autophagy pathway are recruited to the phagosomes of macrophages that engulf dying cells. LAP functions to facilitate the clearance of the cell corpse, and profoundly influences the inflammatory response to dead cell engulfment, decreasing inflammatory cytokine production, increasing anti-inflammatory production, and preventing autoimmunity. We will test the hypothesis that LAP contributes to SLE, and may account for genetic associations of autophagy genes with SLE. Our goals are: 1. To determine if defects in LAP are associated with SLE, and can cause SLE-like disease, 2. To explore how LAP affects specific transcription pathways in phagocytes, and 3. To identify ways in which to control the inflammatory effects of defective LAP. Our studies will identify pharmacologic approaches to “bypassing” the requirement for LAP to control inflammation and autoimmunity, either by enforcing the process of LAP or by engaging the signaling pathways and transcription factors controlled by LAP. We will develop animal models of SLE based on defects in LAP and apply our “bypass” approaches to the treatment of disease in these models.