Efficient detection and clearance of apoptotic cells is essential in the maintenance of tolerance and tissue homeostasis. We recently identified the scavenger receptor expressed on endothelial cells-1 (SCARF1) as the receptor for apoptotic cells on dendritic cells via interactions with C1q/phosphatidylserine complexes on the dead cells (Ramirez-Ortiz et.al.; Nature Immunology). Loss of SCARF1 results in impaired uptake of apoptotic cells in vitro and in vivo, with accumulation of cell corpses in tissues and blood. Consequently, SCARF1 deficient mice develop lupus-like autoimmune disease. In this application, we propose to investigate the role of human SCARF1 in the onset and development of SLE. This is the next logical step in understanding the role of SCARF1 in apoptotic cell clearance, maintenance of tolerance and prevention of autoimmunity. We propose to: 1) Determine whether SCARF1 expression is dysregulated in SLE patients resulting in defects in apoptotic cell recognition and clearance by qRT-PCR, flow cytometry and ImageStream; 2) Define the interactions between SCARF1 with apoptotic cells via biochemical and imaging techniques; 3) Characterize the contribution of SCARF1 activation by C1q and/or apoptotic cells in dendritic cell signaling, maturation and antigen presentation using techniques such as T cell proliferation assay, Luminex analysis of cytokine secretion and confocal imaging techniques. Our preliminary data using cells from healthy volunteers shows that SCARF1 is highly expressed on monocytes and dendritic cells. We anticipate that SCARF1 expression will be downregulated on immune cells of SLE patients, exacerbating and/or accounting for the increased numbers of circulating apoptotic cells found in these patients. The etiology of SLE is unclear, but it is known that development of the disease results from a break in self-tolerance due to deregulated apoptosis or removal of cell corpses. Understanding the role of human SCARF1 in the processes of apoptotic cell recognition and clearance will provide new insight into the regulation of autoimmunity and could lead to the development of new and improved treatment for patients suffering from SLE.
The studies proposed here seek to uncover how the interaction between SCARF1 expressing phagocytes and apoptotic cells shapes the inflammatory responses and regulates the autoimmune disease Systemic Lupus Erythematosus (SLE). We will compare the expression and function of human SCARF1 between healthy individuals and Lupus patients at different stages of the disease. We believe the approaches used in this proposal will provide important new insights into the pathogenesis and predisposing factors to SLE, and will be of significant clinical relevance to other autoimmune and infectious diseases where defects in apoptotic cell clearance may play a role.
|Iram, Tal; Ramirez-Ortiz, Zaida; Byrne, Michael H et al. (2016) Megf10 Is a Receptor for C1Q That Mediates Clearance of Apoptotic Cells by Astrocytes. J Neurosci 36:5185-92|
|Cao, Zhifang; Conway, Kara L; Heath, Robert J et al. (2015) Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation. Immunity 43:715-26|
|Ramirez-Ortiz, Zaida G; Prasad, Amit; Griffith, Jason W et al. (2015) The receptor TREML4 amplifies TLR7-mediated signaling during antiviral responses and autoimmunity. Nat Immunol 16:495-504|