PROJECT SUMMARY Each day billions of cells die and are cleared rapidly with minimal immunological consequence. This process, clearance of apoptotic cells or efferocytosis, is carried out by phagocytes such as macrophages which are numerically fewer in tissues and are often responsible for clearing multiple dead cells and debris in quick succession. Efferocytosis is thought to be important for preventing autoimmunity and inflammatory disease. However, patients suffering from autoimmunity or inflammatory disease rarely present with symptoms expected from a defect in clearance of apoptotic cells, such as excessive accumulation of apoptotic or necrotic cells. On one hand, you have a process that is occurring in every tissue and organ, yet on the other hand, it remains unclear how this process contributes to or prevents autoimmunity and inflammatory disease. We present a new model that suggests autoimmunity and inflammatory disease arise because of disruptions in how macrophages manage apoptotic cell digestion instead of whether or not macrophages engulf at all. This model suggests that efferocytosis is a dangerous process because the content of engulfed apoptotic cells, such as lipids, amino acids, and nucleic acids, can trigger potentially catastrophic inflammatory responses by macrophages. To prevent this, we hypothesize that macrophages use mechanisms to rapidly detect and respond to the engulfed material, termed rapid response circuits (RRCs). This proposal combines novel experimentation with -omics approaches and informatics to identify and assemble putative efferocytosis RRCs, then uses innovative tools and methods to mechanistically study identified efferocytosis RRCs. Using this approach, we will first examine the common efferocytosis RRCs used by macrophages. Then, we will explore unique efferocytosis RRCs used by tissue- resident macrophages who are exposed to dying cells and debris specific to the tissue of residence. Collectively, this work on RRCs will contribute to a new framework for understanding how failure to appropriately digest apoptotic cells contributes to autoimmunity and inflammatory disease, and possibly reveal novel diagnostics and therapeutics.

PROJECT NARRATIVE Clearance of apoptotic cells, termed ‘efferocytosis’, is thought to be essential for preventing autoimmunity and inflammatory disease, yet these illnesses rarely present with defects in ability to clear apoptotic cells. Here, we propose that autoimmunity and inflammatory disease arise because efferocytosis is inherently dangerous, and macrophages (the body’s primary phagocyte) require mechanisms to detect and respond to dangerous engulfed material. We will identify and characterize these mechanisms, termed rapid response circuits, that are used for ‘healthy’ efferocytosis, with the goal of developing a framework for understanding how failure to appropriately digest apoptotic cells contributes to autoimmunity and inflammatory disease.