Role of SCARF1 in Efferocytosis and Prevention of Lupus
Abstract
To maintain homeostasis, the human body generates and eliminates millions of cells daily. In healthy individuals, apoptotic cells are efficiently removed before debris accumulates, avoiding an inflammatory response. However, inefficient clearance of apoptotic cells can result in the accumulation of persistent apoptotic debris, leading to a break in immune tolerance and development of autoimmunity. Indeed, patients with systemic lupus erythematosus (SLE) have high levels of circulating apoptotic cells, indicating a failure in the clearance of dying cells. Uncleared apoptotic cells undergo secondary necrosis, the process in which apoptotic cells disintegrate and release their cellular contents, triggering a cascade of events that initiates an inflammatory response. Additionally, noxious intracellular molecules are released in secondary necrotic cells resulting in autoantibody production, a hallmark feature of lupus. Our current lack of understanding about how immune cells mediate the capture and engulfment of apoptotic cells and the signaling pathways initiated by the accumulation of cellular debris to prevent autoimmunity remains a critical barrier in understanding autoimmune pathogenesis. While it is widely accepted that poor clearance of apoptotic cells plays an important role in lupus development, the molecular mechanisms of apoptotic cell removal and the defects that result in the development of lupus, are largely understudied. Previously, we reported that scavenger receptor class F member 1 (SCARF1) is expressed on dendritic cells and mediates the capture of apoptotic cells. Mice lacking SCARF1 develop lupus-like autoimmune disease with the production of autoantibodies and inflammation in the skin and kidneys, with higher incidence on the female population. The studies proposed here seek to uncover how the interaction between SCARF1-expressing immune cells and apoptotic cells affects the inflammatory response and regulates the development of lupus. Successful completion of the proposed experiments will provide insights into the development of lupus and the flare-ups associated with this disease. We believe the approaches used to characterize SCARF1 will provide important knowledge on the pathogenesis of lupus and its predisposing factors. Lupus is a very heterogeneous disease, affecting multiple systems in the body. Understanding the role of SCARF1 in the removal of apoptotic cells will provide the tool for understanding the SLE disease mechanism. This finding will provide additional insights for new therapies, such as personalized medicine, to target apoptotic cell for removal. Furthermore, the results will be of significant clinical relevance to other autoimmune and infectious diseases where defects in apoptotic cell clearance may play a role.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110803
Entities
People
- Zaida Ramirez-ortiz
Organizations
- United States Army
- University of Massachusetts Medical School