Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Lund, Sweden.
J Leukoc Biol. 2018 Feb;103(2):341-353. doi: 10.1002/JLB.3A0317-110R. Epub 2018 Jan 10.
Galectin-3 is an endogenous β-galactoside-binding lectin comprising a carbohydrate recognition domain (CRD) linked to a collagen-like N-domain. Both domains are required for galectin-3 to induce cellular effects; a C-terminal fragment of galectin-3, galectin-3C, containing the CRD but lacking the N-domain, binds cell surface glycoconjugates but does not induce cellular effects since cross-linking promoted by the N-domain is thought to be required. Instead, galectin-3C is proposed to antagonize the effects of galectin-3 by competing for binding sites. The aim of this study was to investigate the effects of galectin-3C on galectin-3 interactions with human neutrophils. Recombinant galectin-3C inhibited galectin-3-induced production of reactive oxygen species in primed neutrophils. Surprisingly, this inhibition was not due to competitive inhibition of galectin-3 binding to the cells. In contrast, galectin-3C potentiated galectin-3 binding, in line with emerging evidence that galectin-3 can aggregate not only through the N-domain but also through the CRD. The cell surface interaction between galectin-3C and galectin-3 was corroborated by colocalization of fluorescently labeled galectin-3 and galectin-3C. Galectin-3C can be generated in vivo through cleavage of galectin-3 by proteases. Indeed, in circulation, galectin-3 and galectin-3C were both attached to the cell surface of neutrophils, which displayed great capacity to bind additional galectin-3 and galectin-3C. In conclusion, galectin-3C enhances galectin-3 binding to neutrophils by nonactivating type-C self-association, in parallel to inhibiting neutrophil activation by galectin-3 (induced by type-N self-association). This implicates type-C self-association as a termination system for galectin-3-induced cell activation, with the purpose of avoiding oxidant-dependent tissue damage.
半乳糖凝集素-3 是一种内源性的 β-半乳糖苷结合凝集素，由一个糖识别结构域 (CRD) 和一个胶原样 N 结构域相连组成。这两个结构域对于半乳糖凝集素-3 诱导细胞效应都是必需的；半乳糖凝集素-3 的 C 端片段，半乳糖凝集素-3C，包含 CRD 但不包含 N 结构域，可与细胞表面糖缀合物结合，但不会诱导细胞效应，因为 N 结构域促进的交联被认为是必需的。相反，半乳糖凝集素-3C 通过竞争结合位点来拮抗半乳糖凝集素-3 的作用。本研究旨在研究半乳糖凝集素-3C 对半乳糖凝集素-3 与人类中性粒细胞相互作用的影响。重组半乳糖凝集素-3C 抑制了预先刺激的中性粒细胞中半乳糖凝集素-3 诱导的活性氧的产生。令人惊讶的是，这种抑制不是由于半乳糖凝集素-3 与细胞结合的竞争性抑制。相反，半乳糖凝集素-3C 增强了半乳糖凝集素-3 的结合，这与新兴的证据一致，即半乳糖凝集素-3 不仅可以通过 N 结构域，也可以通过 CRD 聚集。半乳糖凝集素-3C 和半乳糖凝集素-3 之间的细胞表面相互作用通过荧光标记的半乳糖凝集素-3 和半乳糖凝集素-3C 的共定位得到证实。半乳糖凝集素-3C 可以通过蛋白酶对半乳糖凝集素-3 的切割在体内产生。事实上，在循环中，半乳糖凝集素-3 和半乳糖凝集素-3C 都附着在中性粒细胞的细胞表面上，这些中性粒细胞具有结合更多半乳糖凝集素-3 和半乳糖凝集素-3C 的巨大能力。总之，半乳糖凝集素-3C 通过非激活的 C 型自组装增强了半乳糖凝集素-3 与中性粒细胞的结合，同时抑制了半乳糖凝集素-3（由 N 型自组装诱导）对中性粒细胞的激活。这意味着 C 型自组装是半乳糖凝集素-3 诱导细胞激活的终止系统，目的是避免氧化依赖的组织损伤。
