Mechanisms of SCARF1 in regulating SLE
In higher organisms, billions of new cells are produced in the body daily and the same number of cells die every day. The effective disposal of dead cells is essential to maintains health. However, if the system that removes dead cells becomes defective, this will lead to an excess of dead cells that are known to cause inflammation and potentially lead to autoimmune diseases, including lupus. Phagocytes, a group of immune cells, are responsible for the removal and disposal of dead cells. Dr. Ramirez-Ortiz previously discovered that phagocytes express a receptor molecule on their cell surface (SCARF1) that detects and removes dead cells. Dr. Ramirez-Ortiz also found that mice without SCARF1 develop lupus-like symptoms similar to what is seen in humans. This latter finding suggests that defective clearance of dead cells may happen when SCARF1 is “broken”. With this grant, Dr. Ramirez-Ortiz will compare SCARF1 on phagocytes from lupus patients and healthy people and look in the blood to see if lupus patients produce autoantibodies against SCARF1. Dr. Ramirez-Ortiz will also develop a mouse model that lacks SCARF1 specifically on phagocytes to test if mice without SCARF1 on these cells develop lupus-like disease.
What this study means for people with lupus
This study will provide new insight on a biological process that may lead to lupus development in humans. Understanding whether SCARF1 is needed to dispose of dead cells in the mouse model and whether this molecule is dysfunctional in lupus patients could lead to the development of new therapeutic approaches that would target defective dead cell removal and/or SCARF1 in patients with lupus.
Clearance of apoptotic cells is arguably the most essential process in the immune system. It is necessary for the homeostatic maintenance of healthy tissue and removal of infected or damaged cells. Professional phagocytes are responsible for removing dying cells; however, defects in the recognition or engulfment of apoptotic cells can lead to chronic inflammation and autoimmune disease. The accumulation of apoptotic cells in tissues has been associated with the autoimmune disease Systemic Lupus Erythematosus (SLE), and several phagocyte receptors responsible for apoptotic cell clearance have been identified. We recently discovered that the scavenger receptor, SCARF1, plays an important role in sensing, and the engulfment of, apoptotic cells. Dendritic cells use SCARF1 to capture apoptotic cells via C1q bound to exposed phosphatidylserine, a primary “eat me” signal that translocates from the inner to the outer leaflet of the cell membrane on dying cells. SCARF1 deficiency in mice leads to the accumulation of apoptotic cells in tissues and the spontaneous development of lupus-like autoimmune disease with the production of autoantibodies to chromatin, aberrant immune cell activation, dermatitis, and nephritis. However, the mechanisms necessary for SCARF1-mediated removal of apoptotic cells and prevention of spontaneous autoimmunity in vivo are not well-understood.
Because apoptotic cell clearance is an essential process to maintain homeostasis, our long-term objective is to identify the mechanisms by which SCARF1 protects from autoimmunity. We hypothesize that SCARF1 expressed on professional phagocytes is vital for the capture and degradation of ACs, in a non-redundant manner, to maintain immune tolerance and prevent autoimmunity. To test our hypothesis, we propose the following aims: 1. To determine whether dysregulated SCARF1 expression in SLE patients is associated with defects in apoptotic cell recognition and disease severity; and 2. To determine the role of cell/tissue-specific SCARF1 deficiency in the spontaneous development of autoimmunity. We will investigate these aims using clinical samples, as well as a newly developed mouse model, which will provide further insight into the cell-specific efferocytosis in SLE. Understanding the mechanisms by which discrete cell populations use SCARF1 to engulf apoptotic cells and prevent inflammation should lay the foundation for the design of novel biological drugs for lupus and other autoimmune disorders.