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Updated: May 16, 2026

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
Published on: December 27, 2016
SIGN-R1, a C-type lectin, enhances apoptotic cell clearance through the complement deposition pathway by interacting
1Department 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.
Insights
SIGN-R1 initiates apoptotic cell clearance by binding to C1q and mediating C3 deposition in the spleen. This process is crucial for systemic immune tolerance and preventing autoimmunity.
Area of Science:
- Immunology
- Cell Biology
Background:
- Marginal zone macrophages (MZMs) and complement proteins (C1q, C3) are vital for clearing apoptotic cells.
- SIGN-R1, a C-type lectin on MZMs, interacts with C1q to combat Streptococcus pneumoniae.
Purpose of the Study:
- To investigate the role of the SIGN-R1-mediated classical complement pathway in apoptotic cell clearance and immune tolerance.
Main Methods:
- Studied the binding of SIGN-R1 to apoptotic cells with and without C1q.
- Analyzed C3 deposition on apoptotic cells in wild-type and SIGN-R1 knockout mice.
- Assessed cytokine secretion and autoantibody levels in response to SIGN-R1 deficiency.
Main Results:
- SIGN-R1 directly binds apoptotic cells, enhanced by C1q, leading to C3 deposition and clearance.
- SIGN-R1 deficiency abolished splenic C3 deposition and delayed apoptotic cell clearance.
- SIGN-R1 deficiency resulted in aberrant cytokine secretion and increased anti-DNA antibody levels.
Conclusions:
- SIGN-R1 initiates a novel mechanism for systemic apoptotic cell clearance via complement activation.
- SIGN-R1 integrates apoptotic cell recognition, complement opsonization, and immune tolerance induction.
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.
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