Identification of a new functional domain of Nogo‐A that promotes inflammatory pain and inhibits neurite growth through binding to NgR1
Identification of a new functional domain of Nogo‐A that promotes inflammatory pain and inhibits neurite growth through binding to NgR1
复制标题
DOI：
10.1096/fj.202000377r
复制
发表时间：
2020-06
期刊：
影响因子：
--
通讯作者：
Huaicun Liu;Dongqiang Su;Lei Liu;Ling Chen;Yan Zhao;S. Chan;Weiguang Zhang;Yun Wang;Jun Wang
中科院分区：
文献类型：
--
作者：
Huaicun Liu;Dongqiang Su;Lei Liu;Ling Chen;Yan Zhao;S. Chan;Weiguang Zhang;Yun Wang;Jun Wang
Nogo-A是轴突再生的关键抑制分子，在其他病理条件下发挥着不同的作用，如中风，精神分裂症和神经退行性疾病。Nogo-66和Nogo-Δ20片段是Nogo-A的两个已知功能结构域，分别通过Nogo-66受体（NgR 1）和鞘氨醇-1-磷酸受体2（S1 PR 2）发挥作用。在这里，我们报告了Nogo‐A的一个新的功能结构域，Nogo‐A aa 846 - 861，在Nogo‐A特异性片段中被鉴定出，该片段促进完全弗氏佐剂（CFA）诱导的炎性疼痛。鞘内注射其拮抗肽846 - 861 PE或特异性抗体可减轻CFA诱导的炎性热痛敏。846 - 861 PE降低背根神经节（DRG）中瞬时受体电位香草酸亚家族成员1（TRPV 1）的含量，并降低DRG神经元对辣椒素的反应。这些作用伴随着LIMK/cofilin磷酸化和肌动蛋白聚合的减少。GST pull-down和荧光共振能量转移（FRET）分析均显示Nogo‐A aa 846 - 861与NgR 1结合。此外，我们证明Nogo‐A aa 846‐861抑制皮质神经元和DRG外植体的神经突生长。我们得出结论，Nogo‐A aa 846‐861是NgR 1的一种新型配体，它激活了抑制轴突生长和促进炎症疼痛的下游信号通路。
Nogo‐A is a key inhibitory molecule to axon regeneration, and plays diverse roles in other pathological conditions, such as stroke, schizophrenia, and neurodegenerative diseases. Nogo‐66 and Nogo‐Δ20 fragments are two known functional domains of Nogo‐A, which act through the Nogo‐66 receptor (NgR1) and sphingosine‐1‐phosphate receptor 2 (S1PR2), respectively. Here, we reported a new functional domain of Nogo‐A, Nogo‐A aa 846‐861, was identified in the Nogo‐A‐specific segment that promotes complete Freund's adjuvant (CFA)‐induced inflammatory pain. Intrathecal injection of its antagonist peptide 846‐861PE or the specific antibody attenuated the CFA‐induced inflammatory heat hyperalgesia. The 846‐861 PE reduced the content of transient receptor potential vanilloid subfamily member 1 (TRPV1) in dorsal root ganglia (DRG) and decreased the response of DRG neurons to capsaicin. These effects were accompanied by a reduction in LIMK/cofilin phosphorylation and actin polymerization. GST pull‐down and fluorescence resonance energy transfer (FRET) assays both showed that Nogo‐A aa 846‐861 bound to NgR1. Moreover, we demonstrated that Nogo‐A aa 846‐861 inhibited neurite outgrowth from cortical neurons and DRG explants. We concluded that Nogo‐A aa 846‐861 is a novel ligand of NgR1, which activates the downstream signaling pathways that inhibit axon growth and promote inflammatory pain.