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SCARF1 in the Pathogenesis of Systemic Lupus Erythematosus

SCARF1 in the Pathogenesis of Systemic Lupus Erythematosus
April Jorge1, Taotao Lao1, Terry K. Means1,2, Zaida G. Ramirez-Ortiz1,3
1 Massachusetts General Hospital. Department of Rheumatology, Allergy and Immunology. Charlestown, MA 02129
2 Sanofi Immunology and Inflammation Research Therapeutic Area. Cambridge, MA 02139
3 University of Massachusetts Medical School. Department of Medicine. Worcester MA 01605

Defects at the cellular level in the detection and clearance of apoptotic cells (ACs) contribute to the pathogenesis of Systemic Lupus Erythematosus (SLE). We previously identified Scavenger Receptor Class F 1 (SCARF1) expressed on dendritic cells (DCs) where it functions as a receptor for C1q and mediates capture and engulfment of apoptotic cells. Deficiency in SCARF1 results in impaired removal of ACs (Figure 1) SCARF1 deficient mice develop a lupus-like autoimmune disease with symptoms similar to human SLE, such as production of anti-nuclear and anti-chromatin antibodies, nephritis and dermatitis. However, the role of human SCARF1 in the removal of ACs is unknown. We hypothesize a dysregulation of SCARF1 in SLE patients results in the accumulation of ACs and contributes to SLE disease activity. In order to identify which cells express SCARF1, we used flow cytometry from healthy donors PBMCs. We found that SCARF1 was highly expressed on DCs and monocytes. Treatment with ACs results in a significant decrease in the cell surface expression of SCARF1. Furthermore, using Nanostring and qPCR, we observed an upregulation in autophagy, TLR, and anti-inflammatory genes in cells expressing high levels of SCARF1. Next, we tested whether soluble SCARF1 (sSCARF1) can interact with ACs. Opsonizing ACs for 30 min with recombinant SCARF1 results in an upregulation of SCARF1 expression measured by flow cytometry and qPCR. Lastly, we obtained serum and PBMCs from SLE patient samples. First, we measured the expression of SCARF1 by flow cytometry in the PMBCs. Unexpectedly, there was no significant difference in SCARF1 expression in the SLE patients compared to healthy donors. Next, we measured the concentration of sSCARF1 in the serum by ELISA. We observed a significant increase in sSCARF1 in the SLE patients compared to control patients. We also detected anti-SCARF1 autoantibodies in 26% of SLE patients, which was associated with dsDNA antibody positivity and higher SLE disease activity. Our data demonstrates that human SCARF1 is an ACs receptor in DCs, playing a role in maintaining tolerance and homeostasis.


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