Leukocyte inflammatory responses provoked by pneumococcal sialidase.
Leukocyte inflammatory responses provoked by pneumococcal sialidase.
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作者：
Chang YC;Uchiyama S;Varki A;Nizet V
据报道，唾液酸的细胞表面表达在免疫细胞激活过程中减少，但这种现象的意义和调节仍在研究中。人类主要细菌病原体肺炎链球菌可引起肺炎、败血症和脑膜炎，通常伴有强烈的炎症反应。肺炎链球菌表达唾液酸酶 (NanA)，有助于粘膜定植、血小板清除和血脑屏障穿透。使用野生型和同基因 NanA 缺陷突变株，我们发现肺炎链球菌 NanA 可以使人 THP-1 单核细胞表面去唾液酸化，导致 ERK 磷酸化增加、NF-κB 激活和促炎细胞因子释放。肺炎链球菌 NanA 表达还刺激人中性粒细胞释放白细胞介素 8 和细胞外陷阱形成。 Siglec-5 细胞内结构域 SHP-2 募集减少和 RNA 干扰研究表明，顺式唾液酸相互作用揭示抑制性 Siglec-5 对 NanA 促炎作用的机制贡献。最后，NanA 增加了肺炎链球菌肺炎鼠鼻内攻击模型中促炎细胞因子的产生。重要性唾液酸装饰所有哺乳动物细胞的表面，在生理、发育和进化中发挥重要作用。 Siglec 是免疫细胞表面的唾液酸结合受体，其中许多与宿主唾液酸聚糖配体发生顺式相互作用，并通过抑制信号的转导抑制炎症反应。最近，某些细菌病原体已被证明可以通过宿主唾液酸结构的分子模拟和抑制性 Siglecs 的参与来抑制白细胞先天免疫反应。我们目前的工作表明，反之亦然，即微生物唾液酸裂解酶可以诱导促炎症反应，该反应部分是通过抑制性 Siglec 的暴露介导的。我们得出的结论是，宿主白细胞准备检测并响应微生物唾液酸酶活性，并产生夸大的炎症反应，这可能对宿主有益或有害，具体取决于感染的部位、阶段和程度。唾液酸装饰所有哺乳动物细胞的表面，在生理、发育和进化中发挥重要作用。 Siglec 是免疫细胞表面的唾液酸结合受体，其中许多与宿主唾液酸聚糖配体发生顺式相互作用，并通过抑制信号的转导抑制炎症反应。最近，某些细菌病原体已被证明可以通过宿主唾液酸结构的分子模拟和抑制性 Siglecs 的参与来抑制白细胞先天免疫反应。我们目前的工作表明，反之亦然，即微生物唾液酸裂解酶可以诱导促炎症反应，该反应部分是通过抑制性 Siglec 的暴露介导的。我们得出的结论是，宿主白细胞准备检测并响应微生物唾液酸酶活性，并产生夸大的炎症反应，这可能对宿主有益或有害，具体取决于感染的部位、阶段和程度。
Cell surface expression of sialic acid has been reported to decrease during immune cell activation, but the significance and regulation of this phenomenon are still being investigated. The major human bacterial pathogen Streptococcus pneumoniae causes pneumonia, sepsis and meningitis, often accompanied by strong inflammatory responses. S. pneumoniae expresses a sialidase (NanA) that contributes to mucosal colonization, platelet clearance, and blood-brain barrier penetration. Using wild-type and isogenic NanA-deficient mutant strains, we showed that S. pneumoniae NanA can desialylate the surface of human THP-1 monocytes, leading to increased ERK phosphorylation, NF-κB activation, and proinflammatory cytokine release. S. pneumoniae NanA expression also stimulates interleukin-8 release and extracellular trap formation from human neutrophils. A mechanistic contribution of unmasking of inhibitory Siglec-5 from cis sialic acid interactions to the proinflammatory effect of NanA is suggested by decreased SHP-2 recruitment to the Siglec-5 intracellular domain and RNA interference studies. Finally, NanA increased production of proinflammatory cytokines in a murine intranasal challenge model of S. pneumoniae pneumonia. Importance Sialic acids decorate the surface of all mammalian cells and play important roles in physiology, development, and evolution. Siglecs are sialic acid-binding receptors on the surface of immune cells, many of which engage in cis interactions with host sialoglycan ligands and dampen inflammatory responses through transduction of inhibitory signals. Recently, certain bacterial pathogens have been shown to suppress leukocyte innate immune responses by molecular mimicry of host sialic acid structures and engagement of inhibitory Siglecs. Our present work shows that the converse can be true, i.e., that a microbial sialic acid-cleaving enzyme can induce proinflammatory responses, which are in part mediated by unmasking of an inhibitory Siglec. We conclude that host leukocytes are poised to detect and respond to microbial sialidase activity with exaggerated inflammatory responses, which could be beneficial or detrimental to the host depending on the site, stage and magnitude of infection. Sialic acids decorate the surface of all mammalian cells and play important roles in physiology, development, and evolution. Siglecs are sialic acid-binding receptors on the surface of immune cells, many of which engage in cis interactions with host sialoglycan ligands and dampen inflammatory responses through transduction of inhibitory signals. Recently, certain bacterial pathogens have been shown to suppress leukocyte innate immune responses by molecular mimicry of host sialic acid structures and engagement of inhibitory Siglecs. Our present work shows that the converse can be true, i.e., that a microbial sialic acid-cleaving enzyme can induce proinflammatory responses, which are in part mediated by unmasking of an inhibitory Siglec. We conclude that host leukocytes are poised to detect and respond to microbial sialidase activity with exaggerated inflammatory responses, which could be beneficial or detrimental to the host depending on the site, stage and magnitude of infection.