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.
Cell Death Differ. 2013 Apr;20(4):535-45. doi: 10.1038/cdd.2012.160. Epub 2012 Dec 14.
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.
补体成分，如 C1q 和 C3，以及脾脏边缘区（MZMs）中的巨噬细胞在有效摄取和处理循环凋亡细胞中发挥关键作用。SIGN-R1 是一种高度表达于 MZMs 亚群中的 C 型凝集素，通过与 C1q 相互作用调节补体固定途径，以抵御血源性肺炎链球菌。因此，我们研究了 SIGN-R1 介导的经典补体途径是否在凋亡细胞清除和免疫耐受中发挥作用。SIGN-R1 首先与凋亡细胞结合，在 C1q 存在的情况下这种结合显著增强。然后，SIGN-R1-C1q 复合物立即介导 C3 在 MZ 中循环凋亡细胞上的沉积，从而有效地清除它们。SIGN-R1 介导的 C3 沉积在 SIGN-R1 敲除（KO）小鼠的脾脏中完全被废除。鉴于 SIGN-R1 不在肝脏中表达，我们发现令人惊讶的是，在野生型小鼠的肝脏中仍发现了 C3 沉积的凋亡细胞，而在 SIGN-R1 KO 肝脏中则显著减少。特别是，SIGN-R1 缺乏导致凋亡细胞清除延迟和细胞因子，如 TNF-α、IL-6 和 TGF-β 在脾脏和肝脏中的异常分泌。此外，与对照小鼠相比，SIGN-R1 耗尽小鼠的抗双链和单链 DNA 抗体水平显著增加。这些发现表明了一种新的凋亡细胞清除机制，该机制由 MZ 中的 SIGN-R1 启动，并确定了 SIGN-R1 在系统清除凋亡细胞中的综合作用，将凋亡细胞的识别、补体的调理作用和免疫耐受的诱导联系起来。
