Department of Infectious Diseases, Research Laboratories, IRCCS, Fondazione San Matteo and University of Pavia, Pavia, Italy.
PLoS One. 2012;7(9):e45821. doi: 10.1371/journal.pone.0045821. Epub 2012 Sep 28.
Sialic acid binding immunoglobulin-like lectin-7 (Siglec-7) is a trans-membrane receptor carrying immunoreceptor tyrosine based inhibitory motifs (ITIMs) and delivering inhibitory signals upon ligation with sialylated glycans. This inhibitory function can be also targeted by several pathogens that have evolved to express sialic acids on their surface to escape host immune responses. Here, we demonstrate that cross-linking of Siglec-7 by a specific monoclonal antibody (mAb) induces a remarkably high production of IL-6, IL-1α, CCL4/MIP-1β, IL-8 and TNF-α. Among the three immune cell subsets known to constitutively express Siglec-7, the production of these pro-inflammatory cytokines and chemokines selectively occurs in monocytes and not in Natural Killer or T lymphocytes. This Siglec-7-mediated activating function is associated with the phosphorylation of the extracellular signal-regulated kinase (ERK) pathway. The present study also shows that sialic acid-free Zymosan yeast particles are able to bind Siglec-7 on monocytes and that this interaction mimics the ability of the anti Siglec-7 mAb to induce the production of pro-inflammatory mediators. Indeed, blocking or silencing Siglec-7 in primary monocytes greatly reduced the production of inflammatory cytokines and chemokines in response to Zymosan, thus confirming that Siglec-7 participates in generating a monocyte-mediated inflammatory outcome following pathogen recognition. The presence of an activating form of Siglec-7 in monocytes provides the host with a new and alternative mechanism to encounter pathogens not expressing sialylated glycans.
唾液酸结合免疫球蛋白样凝集素-7（Siglec-7）是一种跨膜受体，携带免疫受体酪氨酸抑制基序（ITIM），在与唾液酸化糖结合后传递抑制信号。这种抑制功能也可以被几种病原体靶向，这些病原体已经进化出在其表面表达唾液酸，以逃避宿主的免疫反应。在这里，我们证明了通过特异性单克隆抗体（mAb）交联 Siglec-7 会显著诱导 IL-6、IL-1α、CCL4/MIP-1β、IL-8 和 TNF-α 的高产生。在已知组成性表达 Siglec-7 的三种免疫细胞亚群中，这些促炎细胞因子和趋化因子的产生仅发生在单核细胞中，而不在自然杀伤细胞或 T 淋巴细胞中。这种 Siglec-7 介导的激活功能与细胞外信号调节激酶（ERK）途径的磷酸化有关。本研究还表明，无唾液酸的 Zymosan 酵母颗粒能够与单核细胞上的 Siglec-7 结合，这种相互作用模拟了抗 Siglec-7 mAb 诱导促炎介质产生的能力。事实上，在原代单核细胞中阻断或沉默 Siglec-7 会大大减少对 Zymosan 的炎症细胞因子和趋化因子的产生，从而证实 Siglec-7 参与了病原体识别后单核细胞介导的炎症反应。单核细胞中存在激活形式的 Siglec-7 为宿主提供了一种新的替代机制，以应对不表达唾液酸化糖的病原体。
