Ligation of signal inhibitory receptor on leukocytes-1 suppresses the release of neutrophil extracellular traps in systemic lupus erythematosus.
Ligation of signal inhibitory receptor on leukocytes-1 suppresses the release of neutrophil extracellular traps in systemic lupus erythematosus.
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在系统性红斑狼疮中，白细胞 1 上信号抑制受体的连接可抑制中性粒细胞胞外陷阱的释放。
DOI：
10.1371/journal.pone.0078459
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Meyaard L
中科院分区：
文献类型：
--
作者：
Van Avondt K;Fritsch-Stork R;Derksen RH;Meyaard L
中性粒细胞胞外陷阱 (NET) 与系统性红斑狼疮 (SLE) 的发病机制有关，因为网状中性粒细胞释放潜在的免疫原性自身抗原，包括组蛋白、LL37、人中性粒细胞肽 (HNP) 和自身 DNA。反过来，这些 NET 会激活浆细胞样树突状细胞，导致炎症和疾病恶化。如何靶向抑制 NET 形成进行治疗尚未见报道。白细胞信号抑制受体-1 (SIRL-1) 是一种仅在吞噬细胞上表达的表面分子。我们最近发现 SIRL-1 是人类中性粒细胞功能的负调节因子。在这里，我们确定 SIRL-1 的连接是否可以阻止 SLE 中 NET 的致病性释放。新鲜分离来自轻至中度疾病活动性 SLE 患者和健康供体的外周血中性粒细胞。自发地或暴露于抗中性粒细胞抗体或从 SLE 患者获得的血浆后评估 NET 释放。 NET 的形成是通过使用 DNA 染料和 NET 成分的免疫染色进行显微评估以及活细胞成像来确定的。我们发现 SLE 中性粒细胞自发释放 NET。 LL37 抗体的刺激可增强 NET 的形成。抑制烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶活性和 MEK-ERK 信号传导可防止响应这些抗体而释放 NET。通过与抗 SIRL-1 特异性抗体连接来诱导通过抑制性受体 SIRL-1 的信号传导。 SIRL-1 的参与可抑制自发性和抗中性粒细胞抗体诱导的 NET 形成。此外，暴露于 SLE 血浆的健康中性粒细胞的 NET 释放受到 SIRL-1 连接的抑制。因此，SIRL-1 的参与可能通过抑制 NAPDH 氧化酶和 MEK-ERK 活性来抑制 SLE 中自发的和抗中性粒细胞抗体诱导的 NET 形成。总之，这些发现揭示了 SIRL-1 在 NET 形成中的调节作用，可能为打破 SLE 的致病循环提供新的治疗靶点。
Neutrophil extracellular traps (NETs) have been implicated in the pathogenesis of systemic Lupus erythematosus (SLE), since netting neutrophils release potentially immunogenic autoantigens including histones, LL37, human neutrophil peptide (HNP), and self-DNA. In turn, these NETs activate plasmacytoid dendritic cells resulting in aggravation of inflammation and disease. How suppression of NET formation can be targeted for treatment has not been reported yet. Signal Inhibitory Receptor on Leukocytes-1 (SIRL-1) is a surface molecule exclusively expressed on phagocytes. We recently identified SIRL-1 as a negative regulator of human neutrophil function. Here, we determine whether ligation of SIRL-1 prevents the pathogenic release of NETs in SLE. Peripheral blood neutrophils from SLE patients with mild to moderate disease activity and healthy donors were freshly isolated. NET release was assessed spontaneously or after exposure to anti-neutrophil antibodies or plasma obtained from SLE patients. The formation of NETs was determined by microscopic evaluation using DNA dyes and immunostaining of NET components, as well as by live cell imaging. We show that SLE neutrophils spontaneously release NETs. NET formation is enhanced by stimulation with antibodies against LL37. Inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and MEK-ERK signaling prevents NET release in response to these antibodies. Signaling via the inhibitory receptor SIRL-1 was induced by ligation with anti-SIRL-1 specific antibodies. Both spontaneous and anti-neutrophil antibody-induced NET formation is suppressed by engagement of SIRL-1. Furthermore, NET release by healthy neutrophils exposed to SLE plasma is inhibited by SIRL-1 ligation. Thus, SIRL-1 engagement can dampen spontaneous and anti-neutrophil antibody-induced NET formation in SLE, likely by suppressing NAPDH oxidase and MEK-ERK activity. Together, these findings reveal a regulatory role for SIRL-1 in NET formation, potentially providing a novel therapeutic target to break the pathogenic loop in SLE.
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DOI：
10.1084/jem.20021553
发表时间：
2003-03-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bennett L;Palucka AK;Arce E;Cantrell V;Borvak J;Banchereau J;Pascual V
通讯作者：
Pascual V
影响因子：
44.1
作者：
Remijsen, Quinten;Vanden Berghe, Tom;Vandenabeele, Peter
通讯作者：
Vandenabeele, Peter
影响因子：
2.6
作者：
Petri, M;Buyon, J;Kim, M
通讯作者：
Kim, M
影响因子：
14.8
作者：
Hakkim, Abdul;Fuchs, Tobias A.;Waldmann, Herbert
通讯作者：
Waldmann, Herbert
中性粒细胞弹性酶和髓过氧化物酶调节中性粒细胞外陷阱的形成。
DOI：
10.1083/jcb.201006052
发表时间：
2010-11-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Papayannopoulos V;Metzler KD;Hakkim A;Zychlinsky A
通讯作者：
Zychlinsky A