SCARF1-induced efferocytosis plays an immunomodulatory role in humans April M. Jorge1,2, Taotao Lao3, Rachel Kim3, Joseph ElKhoury3, Terry K. Means3,4, Zaida G. Ramirez-Ortiz3,5* 1 Clinical Epidemiology Program of the Division of Rheumatology, Allergy, and Immunology and Mongan Institute, Department of Medicine, Massachusetts General Hospital, 100 Cambridge Street, Suite 1600, Boston, MA 02114 2 Rheumatology Unit, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, 55 Fruit Street, Yawkey 2C, Boston, MA 02114 3 Center for Immunology and Inflammatory Diseases. Department of Rheumatology, Allergy and Immunology. Massachusetts General Hospital. 13st CNY 149, Charlestown MA 02129 4 Sanofi, Autoimmunity Cluster, Immunology & Inflammation Research Therapeutic Area. 270 Albany Street Room 2427-A, Cambridge MA 02139 5 Department of Medicine, Division of Infectious Diseases and Immunology. University of Massachusetts Medical School. 364 Plantation St. LRB319, Worcester MA 01605 *Corresponding/Presenting author Abstract Deficiency in the clearance of cellular debris is a major pathogenic factor in the emergence of autoimmune diseases. We previously demonstrated that mice deficient for scavenger receptor class F member 1 (SCARF1) develop a lupus-like autoimmune disease with symptoms similar to human systemic lupus erythematosus (SLE), including a pronounced accumulation of apoptotic cells (ACs). Therefore, we hypothesized that SCARF1 will be important for clearance of ACs and maintenance of self-tolerance in humans, and that dysregulation of this process could contribute to SLE. Here, we show that SCARF1 is highly expressed on phagocytic cells, where it functions as an efferocytosis receptor. In healthy individuals, we discovered that engagement of SCARF1 by ACs on BDCA1+ dendritic cells (DCs) is responsible for initiating an anti-inflammatory response mediated by IL-10 induction via the phosphorylation of signal transducer and activator of transcription 1 (STAT1). Furthermore, soluble SCARF1 functions as an opsonizing agent enhancing the capture and immediate removal of ACs. Our data demonstrate that human SCARF1 is an AC receptor in DCs and plays a role in maintaining tolerance and homeostasis.