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-a, IL-6, and TGF-b 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.

Plasminogen promotes macrophage phagocytosis in mice

“…However, the number of marginal zone macrophages, identified as SIGNR1 positive cells, 14 was similar in Plg 2/2 and Plg 1/1 mice (supplemental Figure 3A-B). These data demonstrate that Plg is required for efficient phagocytic clearance of apoptotic thymocytes from the circulation by splenic macrophages.…”

Elimination of Nucleoproteins in Systemic Lupus Erythematosus and Antinuclear Autoantibodies Production

“…They opsonize chromatin and keep it soluble, thus promoting digestion of long chromatin segments, transportation through circulation, and further recognition by macrophages [64]. The terminal points of this transfer are mononuclear phagocyte cells, primarily in the liver and spleen [65]. Overall eiciency of this elimination mechanism is quite high, since after injection of considerable amount of exogenous DNA, or after spontaneous release of endogenous nucleoproteins during hemodialysis, half-life of the DNA in circulation is within 4-15 min [66].…”

Systemic Clearance of Radiation-Induced Apoptotic Cells by SIGN-R1 and Complement Factors and their Involvement in Autoimmune Diseases

“…Although the aim of radiotherapy is to induce apoptotic and non-apoptotic cell death in cancer cells, radiotherapy inadvertently results in the damage of normal tissues [2][3][4]. Among tissues, lymphoid organs including the lymph nodes, thymus, and spleen, are highly radiation-sensitive [5].…”

“…SIGN-R1 directly binds to C1q and mediates the opsonization of C3 on blood-borne Streptococcus pneumoniae, dominantly regulating the immunoglobulin-independent classical complement pathway [14]. Also, SIGN-R1 directly binds to apoptotic cells, being enhanced by interacting with C1q [3]. And then, the SIGN-R1-C1q complex immediately mediates C3 deposition on apoptotic cells, thus promoting their systemic clearance and maintaining immune tolerance in vivo ( Figure 1) [3].…”

“…Also, SIGN-R1 directly binds to apoptotic cells, being enhanced by interacting with C1q [3]. And then, the SIGN-R1-C1q complex immediately mediates C3 deposition on apoptotic cells, thus promoting their systemic clearance and maintaining immune tolerance in vivo ( Figure 1) [3].…”