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The scavenger receptor SCARF1 mediates the clearance of apoptotic cells and prevents autoimmunity

Abstract

The clearance of apoptotic cells is critical for the control of tissue homeostasis; however, the full range of receptors on phagocytes responsible for the recognition of apoptotic cells remains to be identified. Here we found that dendritic cells (DCs), macrophages and endothelial cells used the scavenger receptor SCARF1 to recognize and engulf apoptotic cells via the complement component C1q. Loss of SCARF1 impaired the uptake of apoptotic cells. Consequently, in SCARF1-deficient mice, dying cells accumulated in tissues, which led to a lupus-like disease, with the spontaneous generation of autoantibodies to DNA-containing antigens, activation of cells of the immune system, dermatitis and nephritis. The discovery of such interactions of SCARF1 with C1q and apoptotic cells provides insight into the molecular mechanisms involved in the maintenance of tolerance and prevention of autoimmune disease.

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Figure 1: SCARF1 mediates the recognition of apoptotic cells.
Figure 2: SCARF1 binds C1q.
Figure 3: Impaired engulfment of apoptotic cells by SCARF1-deficient CD8α+ DCs.
Figure 4: SCARF1 is necessary for the uptake of apoptotic cells.
Figure 5: SCARF1 is necessary for the homeostatic clearance of apoptotic cells in vivo.
Figure 6: Generation of autoantibodies by Scarf1−/− mice.
Figure 7: Enhanced immunological activation in Scarf1−/− mice.
Figure 8: Lupus nephritis in Scarf1−/− mice.

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Acknowledgements

We thank Y.F. Peng (University of Washington) for Mfge8−/− mice; M. Michalak (University of Alberta) for K41 (calreticulin-sufficient) and K42 (calreticulin-deficient) MEFs; and M.J. Shlomchik and P. Mundel and members of their laboratories for technical assistance and discussions. Supported by the National Institute of Allergy and Infectious Diseases (R01-AI084884 to T.K.M.; U24 AI082660 to J.E.K.; and T32-AI007061 to Z.G.R.-O.), the National Institute of Arthritis, Musculoskeletal and Skin Diseases (K01-AR051367 to T.K.M.), the National Institute of Diabetes and Digestive and Kidney Diseases (F32-DK097891 to W.F.P.), the Lupus Research Institute (T.K.M. and N.H.), the Alliance for Lupus Research (T.K.M. and N.H.) and the American Society of Nephrology (W.F.P.).

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T.K.M., Z.G.R.-O. and W.F.P. planned the research, analyzed and interpreted data and wrote the manuscript; Z.G.R.-O. did most of the experiments; C.J.B. helped with mouse breeding and genotyping; W.F.P., A.P. and T.I. did and analyzed ELISA, PCR and mouse-pathology studies; N.H. and A.D.L. analyzed and interpreted data; T.K.M., J.E.K., and M.H.B. contributed to the generation of SCARF1-deficient mice; and all authors participated in editing the manuscript.

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Correspondence to Terry K Means.

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Ramirez-Ortiz, Z., Pendergraft, W., Prasad, A. et al. The scavenger receptor SCARF1 mediates the clearance of apoptotic cells and prevents autoimmunity. Nat Immunol 14, 917–926 (2013). https://doi.org/10.1038/ni.2670

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