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

Abstract

Clearance of apoptotic cells is critical for control of tissue homeostasis however the full range of receptor(s) on phagocytes responsible for recognition of apoptotic cells remains to be identified. Here we show that dendritic cells (DCs), macrophages and endothelial cells use scavenger receptor type F family member 1 (SCARF1) to recognize and engulf apoptotic cells via C1q. Loss of SCARF1 impairs uptake of apoptotic cells. Consequently, in SCARF1-deficient mice, dying cells accumulate in tissues leading to a lupus-like disease with the spontaneous generation of autoantibodies to DNA-containing antigens, immune cell activation, dermatitis and nephritis. The discovery of SCARF1 interactions with C1q and apoptotic cells provides insights into molecular mechanisms involved in maintenance of tolerance and prevention of autoimmune disease.Clearance of apoptotic cells is one of the most important processes of the immune system and is necessary for the homeostatic maintenance of healthy tissues and removal of infected or damaged cells [1][2][3] . Several types of cells are capable of apoptotic cell uptake, including Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms * Correspondence and requests for materials should be addressed to: T.K. M. means.terry@mgh.harvard.edu, 617-726-6497). Note: Supplementary information is available on the Nature Immunology website. AUTHORS CONTRIBUTIONS T.K.M., Z.G.R., and W.F.P. III planned the research, analyzed and interpreted data and wrote the manuscript. Z.G.R. performed most of the experiments. C.J.B helped with mouse breeding and genotyping. W.F.P. III, A.P., and T.I. performed and analyzed ELISAs, PCR, and mouse pathology. 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. All authors participated in editing the manuscript into its final form. COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript both professional scavengers (macrophages, DCs) and non-professional phagocytes (fibroblasts, endothelial, and epithelial cells). In vivo, phagocytes are responsible for the rapid removal of dying cells before necrosis, a post-apoptotic stage accompanied by loss of membrane integrity and leakage of noxious intracellular molecules into the surrounding tissues 4,5 . Phagocyte engulfment of apoptotic cells occurs via an immunologically silent process by activating immunosuppressive pathways and the production of anti-inflammatory cytokines to prevent an immune response against self-antigens 6 . Consequently, defects in recognition and/or engulfment of apoptotic cells can lead to chronic inflammatory diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, glomerulonephritis and at...

Apoptotic cell-derived membrane microparticles and IFN-α induce an inflammatory immune response

“…Blockage of SCARF1 by a blocking antibody resulted in a significant reduction in phagocytosis. A similar mechanism has been shown in uptake of apoptotic cells (Ramirez-Ortiz et al, 2013) by dendritic cells. Not only did SCARF1-deficient mice show a despaired removal of apoptotic cells, but also with time Ramirez-Ortiz et al were able to detect autoantibodies typical for SLE in those SCARF1-deficient mice.…”

“…The exposure of phosphatidylserine (PtdSer) on the cell surface is a hallmark feature of apoptosis (Fadok et al, 2001) and several factors have been shown to be involved in uptake of apoptotic cells by binding to PtdSer, such as brain-specific angiogenesis inhibitor 1 (BAI1) (Park et al, 2007) and factors of the T-cell immunoglobulin mucin (TIM) family (Kobayashi et al, 2007). In addition, factors such as scavenger receptor 1 (SCARF1; originally called scavenger receptor expressed by endothelial cell 1, SREC-1) have been shown to facilitate phagocytosis of apoptotic cells through PtdSer-independent pathways (Ramirez-Ortiz et al, 2013). Although uptake of apoptotic cells has been focus of intensive research, little is known about the mechanisms of AdMP uptake.…”

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“…Earlier, the general opinion was that scavenger receptors are highly atherogenic by producing massive cholesterol depositions in the blood vessel intima 23,55) . Today, it is known that scavenger function also regulates apoptotic cell clearance, thus maintaining vascular wall homeostasis 56) . However, further in vitro experiments showed that macrophages from CXCL16-deficient mice internalize apoptotic thymocytes equally well compared with those in control mice, which brought into question the proposed atheroprotective mechanism.…”