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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References
Elliott, M.R. & Ravichandran, K.S. Clearance of apoptotic cells: implications in health and disease. J. Cell Biol. 189, 1059–1070 (2010).
Devitt, A. & Marshall, L.J. The innate immune system and the clearance of apoptotic cells. J. Leukoc. Biol. 90, 447–457 (2011).
Lauber, K., Blumenthal, S.G., Waibel, M. & Wesselborg, S. Clearance of apoptotic cells: getting rid of the corpses. Mol. Cell 14, 277–287 (2004).
Erwig, L.P. & Henson, P.M. Clearance of apoptotic cells by phagocytes. Cell Death Differ. 15, 243–250 (2008).
Munoz, L.E. et al. Apoptosis in the pathogenesis of systemic lupus erythematosus. Lupus 17, 371–375 (2008).
Ravichandran, K.S. & Lorenz, U. Engulfment of apoptotic cells: signals for a good meal. Nat. Rev. Immunol. 7, 964–974 (2007).
Nagata, S., Hanayama, R. & Kawane, K. Autoimmunity and the clearance of dead cells. Cell 140, 619–630 (2010).
Shao, W.H. & Cohen, P.L. Disturbances of apoptotic cell clearance in systemic lupus erythematosus. Arthritis Res. Ther. 13, 202 (2011).
Fadok, V.A. et al. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J. Immunol. 148, 2207–2216 (1992).
Kobayashi, N. et al. TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 27, 927–940 (2007).
Park, D. et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450, 430–434 (2007).
Hanayama, R. et al. Identification of a factor that links apoptotic cells to phagocytes. Nature 417, 182–187 (2002).
Païdassi, H. et al. C1q binds phosphatidylserine and likely acts as a multiligand-bridging molecule in apoptotic cell recognition. J. Immunol. 180, 2329–2338 (2008).
Païdassi, H. et al. Investigations on the C1q-calreticulin-phosphatidylserine interactions yield new insights into apoptotic cell recognition. J. Mol. Biol. 408, 277–290 (2011).
Galvan, M.D., Greenlee-Wacker, M.C. & Bohlson, S.S. C1q and phagocytosis: the perfect complement to a good meal. J. Leukoc. Biol. 92, 489–497 (2012).
Gardai, S.J. et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123, 321–334 (2005).
Manderson, A.P., Botto, M. & Walport, M.J. The role of complement in the development of systemic lupus erythematosus. Annu. Rev. Immunol. 22, 431–456 (2004).
Hanayama, R. et al. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304, 1147–1150 (2004).
Taylor, P.R. et al. A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J. Exp. Med. 192, 359–366 (2000).
Mukhopadhyay, S., Pluddemann, A. & Gordon, S. Macrophage pattern recognition receptors in immunity, homeostasis and self tolerance. Adv. Exp. Med. Biol. 653, 1–14 (2009).
Adachi, H., Tsujimoto, M., Arai, H. & Inoue, K. Expression cloning of a novel scavenger receptor from human endothelial cells. J. Biol. Chem. 272, 31217–31220 (1997).
Tamura, Y. et al. Scavenger receptor expressed by endothelial cells I (SREC-I) mediates the uptake of acetylated low density lipoproteins by macrophages stimulated with lipopolysaccharide. J. Biol. Chem. 279, 30938–30944 (2004).
Berwin, B., Delneste, Y., Lovingood, R.V., Post, S.R. & Pizzo, S.V. SREC-I, a type F scavenger receptor, is an endocytic receptor for calreticulin. J. Biol. Chem. 279, 51250–51257 (2004).
Jeannin, P. et al. Complexity and complementarity of outer membrane protein A recognition by cellular and humoral innate immunity receptors. Immunity 22, 551–560 (2005).
Hölzl, M.A. et al. The zymogen granule protein 2 (GP2) binds to scavenger receptor expressed on endothelial cells I (SREC-I). Cell. Immunol. 267, 88–93 (2011).
Murshid, A., Gong, J. & Calderwood, S.K. Heat shock protein 90 mediates efficient antigen cross presentation through the scavenger receptor expressed by endothelial cells-I. J. Immunol. 185, 2903–2917 (2010).
Means, T.K. et al. Evolutionarily conserved recognition and innate immunity to fungal pathogens by the scavenger receptors SCARF1 and CD36. J. Exp. Med. 206, 637–653 (2009).
Rechner, C., Kuhlewein, C., Muller, A., Schild, H. & Rudel, T. Host glycoprotein Gp96 and scavenger receptor SREC interact with PorB of disseminating Neisseria gonorrhoeae in an epithelial invasion pathway. Cell Host Microbe 2, 393–403 (2007).
Zhou, Z., Hartwieg, E. & Horvitz, H.R. CED-1 is a transmembrane receptor that mediates cell corpse engulfment in C. elegans. Cell 104, 43–56 (2001).
Means, T.K. Fungal pathogen recognition by scavenger receptors in nematodes and mammals. Virulence 1, 37–41 (2010).
Ishii, J. et al. SREC-II, a new member of the scavenger receptor type F family, trans-interacts with SREC-I through its extracellular domain. J. Biol. Chem. 277, 39696–39702 (2002).
Yoshiizumi, K., Nakajima, F., Dobashi, R., Nishimura, N. & Ikeda, S. Studies on scavenger receptor inhibitors. Part 1: synthesis and structure-activity relationships of novel derivatives of sulfatides. Bioorg. Med. Chem. 10, 2445–2460 (2002).
Iyoda, T. et al. The CD8+ dendritic cell subset selectively endocytoses dying cells in culture and in vivo. J. Exp. Med. 195, 1289–1302 (2002).
Tan, E.M. et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 25, 1271–1277 (1982).
Tsokos, G.C. Systemic lupus erythematosus. N. Engl. J. Med. 365, 2110–2121 (2011).
Casciola-Rosen, L.A., Anhalt, G. & Rosen, A. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J. Exp. Med. 179, 1317–1330 (1994).
Zandman-Goddard, G., Peeva, E. & Shoenfeld, Y. Gender and autoimmunity. Autoimmun. Rev. 6, 366–372 (2007).
Xu, Y. et al. Pleiotropic IFN-dependent and -independent effects of IRF5 on the pathogenesis of experimental lupus. J. Immunol. 188, 4113–4121 (2012).
Winfield, J.B., Faiferman, I. & Koffler, D. Avidity of anti-DNA antibodies in serum and IgG glomerular eluates from patients with systemic lupus erythematosus. Association of high avidity antinative DNA antibody with glomerulonephritis. J. Clin. Invest. 59, 90–96 (1977).
Reddien, P.W., Cameron, S. & Horvitz, H.R. Phagocytosis promotes programmed cell death in C. elegans. Nature 412, 198–202 (2001).
Awasaki, T. et al. Essential role of the apoptotic cell engulfment genes draper and ced-6 in programmed axon pruning during Drosophila metamorphosis. Neuron 50, 855–867 (2006).
Hamon, Y. et al. Cooperation between engulfment receptors: the case of ABCA1 and MEGF10. PLoS ONE 1, e120 (2006).
Su, H.P. et al. Interaction of CED-6/GULP, an adapter protein involved in engulfment of apoptotic cells with CED-1 and CD91/low density lipoprotein receptor-related protein (LRP). J. Biol. Chem. 277, 11772–11779 (2002).
Wu, H.H. et al. Glial precursors clear sensory neuron corpses during development via Jedi-1, an engulfment receptor. Nat. Neurosci. 12, 1534–1541 (2009).
Scheib, J.L., Sullivan, C.S. & Carter, B.D. Jedi-1 and MEGF10 signal engulfment of apoptotic neurons through the tyrosine kinase Syk. J. Neurosci. 32, 13022–13031 (2012).
Ogden, C.A. et al. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J. Exp. Med. 194, 781–795 (2001).
Botto, M. et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat. Genet. 19, 56–59 (1998).
Wong, K. et al. Phosphatidylserine receptor Tim-4 is essential for the maintenance of the homeostatic state of resident peritoneal macrophages. Proc. Natl. Acad. Sci. USA 107, 8712–8717 (2010).
Cohen, P.L. et al. Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J. Exp. Med. 196, 135–140 (2002).
Miyanishi, M., Segawa, K. & Nagata, S. Synergistic effect of Tim4 and MFG-E8 null mutations on the development of autoimmunity. Int. Immunol. 24, 551–559 (2012).
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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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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DOI: https://doi.org/10.1038/ni.2670
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