title: SIGN-R1, a C-type lectin, enhances apoptotic cell clearance through the complement deposition pathway by interacting with C1q in the spleen.
abstract: Complements, such as C1q and C3, and macrophages in the splenic marginal zone (MZMs) play pivotal roles in the efficient uptake and processing of circulating apoptotic cells. SIGN-R1, a C-type lectin that is highly expressed in a subpopulation of MZMs, regulates the complement fixation pathway by interacting with C1q, to fight blood-borne Streptococcus pneumoniae. Therefore, we examined whether the SIGN-R1-mediated classical complement pathway plays a role in apoptotic cell clearance and immune tolerance. SIGN-R1 first-bound apoptotic cells and this binding was significantly enhanced in the presence of C1q. SIGN-R1-C1q complex then immediately mediated C3 deposition on circulating apoptotic cells in the MZ, leading to the efficient clearance of them. SIGN-R1-mediated C3 deposition was completely abolished in the spleen of SIGN-R1 knockout (KO) mice. Given that SIGN-R1 is not expressed in the liver, we were struck by the finding that C3-deposited apoptotic cells were still found in the liver of wild-type mice, and dramatically reduced in the SIGN-R1 KO liver. In particular, SIGN-R1 deficiency caused delayed clearance of apoptotic cells and aberrant secretion of cytokines, such as TNF-α, IL-6, and TGF-β in the spleen as well as in the liver. In addition, anti-double- and single-stranded DNA antibody level was significantly increased in SIGN-R1-depleted mice compared with control mice. These findings suggest a novel mechanism of apoptotic cell clearance which is initiated by SIGN-R1 in the MZ and identify an integrated role of SIGN-R1 in the systemic clearance of apoptotic cells, linking the recognition of apoptotic cells, the opsonization of complements, and the induction of immune tolerance.
authors.affiliation: Department of Biomedical Science and Technology, SMART Institute of Advanced Biomedical Science, Institute of Functional Genomics, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
authors.forename: M G
authors.initials: MG
authors.lastname: Prabagar
authors.forename: Y
authors.initials: Y
authors.lastname: Do
authors.forename: S
authors.initials: S
authors.lastname: Ryu
authors.forename: J-Y
authors.initials: JY
authors.lastname: Park
authors.forename: H-J
authors.initials: HJ
authors.lastname: Choi
authors.forename: W-S
authors.initials: WS
authors.lastname: Choi
authors.forename: T J
authors.initials: TJ
authors.lastname: Yun
authors.forename: J
authors.initials: J
authors.lastname: Moon
authors.forename: I-S
authors.initials: IS
authors.lastname: Choi
authors.forename: K
authors.initials: K
authors.lastname: Ko
authors.forename: K
authors.initials: K
authors.lastname: Ko
authors.forename: C
authors.initials: C
authors.lastname: Young Shin
authors.forename: C
authors.initials: C
authors.lastname: Cheong
authors.forename: Y-S
authors.initials: YS
authors.lastname: Kang
mesh_terms: D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015922:Complement C1q / Q000378:metabolism*; D003176:Complement C3 / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004277:DNA, Single-Stranded / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D019169:Jurkat Cells; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000378:metabolism*; D060168:Thymocytes / Q000166:cytology / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D015922:Complement C1q; D003176:Complement C3; D004277:DNA, Single-Stranded; D016753:Interleukin-10; D015850:Interleukin-6; D037181:Lectins, C-Type; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin