Mannose-binding lectin recognizes peptidoglycan via the N-acetyl glucosamine moiety, and inhibits ligand-induced proinflammatory effect and promotes chemokine production by macrophages
Mannose-binding lectin recognizes peptidoglycan via the N-acetyl glucosamine moiety, and inhibits ligand-induced proinflammatory effect and promotes chemokine production by macrophages
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DOI：
10.4049/jimmunol.175.3.1785
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发表时间：
2005-08-01
影响因子：
4.4
通讯作者：
Palaniyar, N
中科院分区：
文献类型：
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作者：
Nadesalingam, J;Dodds, AW;Palaniyar, N
肽聚糖（PGN）是革兰氏阳性菌细胞壁的主要成分（占90%，w/w），由N - 乙酰葡糖胺（GlcNAc）和N - 乙酰胞壁酸（MurNAc）二糖重复单元组成，这些单元通过短肽交联。我们假设PGN是病原体相关模式识别蛋白的一种配体。甘露糖结合凝集素（MBL）和血清淀粉样成分P是血液中存在的两种碳水化合物结合的先天免疫蛋白。在这项研究中，我们表明人MBL（而非血清淀粉样成分P）通过其C型凝集素结构域与PGN显著结合，并且GlcNAc比MurNAc更能有效地竞争这种相互作用。表面等离子体共振分析表明，天然MBL以高亲和力结合固定化的PGN。竞争实验还表明，天然MBL和MBL(n/CRD)（一种含颈部和碳水化合物识别结构域的48 kDa重组三聚体MBL片段）对GlcNAc的亲和力高于对MurNAc的亲和力。蛋白质芯片和酶联免疫吸附测定（ELISA）表明，PGN可增加佛波酯（PMA）刺激的人单核细胞U937细胞中肿瘤坏死因子 -α（TNF -α）、白细胞介素 - 8（IL - 8）、白细胞介素 - 10（IL - 10）、单核细胞趋化蛋白 - 2（MCP - 2）和调节活化正常T细胞表达和分泌的趋化因子（RANTES）的分泌。有趣的是，MBL与PGN同时存在会增加IL - 8和RANTES的产生，但会减少TNF -α的产生。我们的结果表明，革兰氏阳性菌是MBL具有生物学相关性的配体，并且胶原凝集素通过其C型凝集素结构域优先结合PGN的GlcNAc部分。MBL抑制PGN诱导的促炎细胞因子的产生，同时增强巨噬细胞趋化因子的产生，这表明MBL可能下调巨噬细胞介导的炎症，同时增强吞噬细胞的募集。
Peptidoglycan (PGN) is the major cell wall component (90%, w/w) of Gram-positive bacteria and consists of N-acetylglucosamine (GIcNAc) and N-acetylmuramic acid (MurNAc) disaccharide repeating arrays that are cross-linked by short peptides. We hypothesized that PGN is a ligand for pathogen-associated pattern-recognition proteins. Mannose-binding lectin (MBL) and serum amyloid component P are two carbohydrate-binding innate immune proteins present in the blood. In this study we show that human MBL, but not serum amyloid component P, binds significantly to PGN via its C-type lectin domains, and that the interaction can be more effectively competed by GlcNAc than by MurNAc. Surface plasmon resonance analyses show that native MBL binds immobilized PGN with high avidity. Competition experiments also show that both native MBL and MBL(n/CRD), a 48-kDa recombinant trimeric fragment of MBL containing neck and carbohydrate recognition domains, have higher affinity for GIcNAc than for MurNAc. Protein arrays and ELISA show that PGN increases the secretion of TNF-alpha, IL-8, IL-10, MCP-2, and RANTES from PMA-stimulated human monocytic U937 cells. Interestingly, the presence of MBL together with PGN increases the production of IL-8 and RANTES, but reduces that of TNF-alpha. Our results indicate that Gram-positive bacterial is a biologically relevant ligand for MBL, and that the collectin preferentially binds to the GIcNAc moiety of the PGN via its C-type lectin domains. MBL inhibits PGN-induced production of proinflammatory cytokines while enhancing the production of chemokines by macrophages, which suggests that MBL may down-regulate macrophage-mediated inflammation while enhancing phagocyte recruitment.