The alternatively spliced fibronectin CS1 isoform regulates IL-17A levels and mechanical allodynia after peripheral nerve injury.
The alternatively spliced fibronectin CS1 isoform regulates IL-17A levels and mechanical allodynia after peripheral nerve injury.
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DOI：
10.1186/s12974-015-0377-6
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发表时间：
2015-09-04
影响因子：
9.3
通讯作者：
Shubayev VI
中科院分区：
文献类型：
--
作者：
Liu H;Dolkas J;Hoang K;Angert M;Chernov AV;Remacle AG;Shiryaev SA;Strongin AY;Nishihara T;Shubayev VI
与周围神经物理损伤相关的机械性疼痛过敏依赖于表达疼痛细胞因子白介素17A的辅助性T细胞。纤维连接蛋白(FN)亚型在编码25个残基的连接片段1(CS1)的IIICS区域内交替剪接，调节T细胞向炎症部位的募集。在此，我们分析了含有CS1的FN(FN-CS1)在周围神经损伤后IL-17A表达和疼痛中的作用。采用质谱学、免疫印迹和FN-CS1特异性免疫荧光分析等方法检测大鼠坐骨神经慢性压迫损伤后FN的表达。采用FN-CS1/α4整合素结合的竞争性抑制剂FN-CS1多肽急性坐骨神经内注射的方法，探讨FN-CS1在机械和热痛过敏及IL-17A表达(Taqman RT-PCR法)中的功能意义。原代培养雪旺细胞是CCI神经中FN-CS1的主要来源。CCI后，FN在坐骨神经中的表达增加，FN-CS1主要沉积在内皮细胞、雪旺细胞和巨噬细胞中。急性CS1治疗可减轻机械性异位痛觉(来自无害刺激的疼痛)，但不能减轻热痛觉过敏，并降低受损神经中IL-17A的表达水平。CS1肽抑制内毒素或饥饿刺激的应激许旺细胞ERK/MAPK通路的激活。在周围神经物理损伤后，FN-CS1通过增加表达IL-17A的细胞(可能是Th17)的数量而促进机械性疼痛过敏。CS1多肽疗法可用于神经病理性疼痛的药理控制。本文的在线版本(doi：10.1186/s12974-0150377-6)包含补充材料，授权用户可以使用。
Mechanical pain hypersensitivity associated with physical trauma to peripheral nerve depends on T-helper (Th) cells expressing the algesic cytokine, interleukin (IL)-17A. Fibronectin (FN) isoform alternatively spliced within the IIICS region encoding the 25-residue-long connecting segment 1 (CS1) regulates T cell recruitment to the sites of inflammation. Herein, we analyzed the role of CS1-containing FN (FN-CS1) in IL-17A expression and pain after peripheral nerve damage. Mass spectrometry, immunoblotting, and FN-CS1-specific immunofluorescence analyses were employed to examine FN expression after chronic constriction injury (CCI) in rat sciatic nerves. The acute intra-sciatic nerve injection of the synthetic CS1 peptide (a competitive inhibitor of the FN-CS1/α4 integrin binding) was used to elucidate the functional significance of FN-CS1 in mechanical and thermal pain hypersensitivity and IL-17A expression (by quantitative Taqman RT-PCR) after CCI. The CS1 peptide effects were analyzed in cultured primary Schwann cells, the major source of FN-CS1 in CCI nerves. Following CCI, FN expression in sciatic nerve increased with the dominant FN-CS1 deposition in endothelial cells, Schwann cells, and macrophages. Acute CS1 therapy attenuated mechanical allodynia (pain from innocuous stimulation) but not thermal hyperalgesia and reduced the levels of IL-17A expression in the injured nerve. CS1 peptide inhibited the LPS- or starvation-stimulated activation of the stress ERK/MAPK pathway in cultured Schwann cells. After physical trauma to the peripheral nerve, FN-CS1 contributes to mechanical pain hypersensitivity by increasing the number of IL-17A-expressing (presumably, Th17) cells. CS1 peptide therapy can be developed for pharmacological control of neuropathic pain. The online version of this article (doi:10.1186/s12974-015-0377-6) contains supplementary material, which is available to authorized users.