CCL17：一種具有多生物學(xué)功能的趨化因子
日期：2025-06-09 09:38:02
1. CCL17概述
CCL17（也稱為TARC）是一種屬于CC亞家族的趨化因子，主要參與免疫細(xì)胞的遷移、激活和炎癥反應(yīng)的調(diào)節(jié)。它由樹突狀細(xì)胞、內(nèi)皮細(xì)胞、角質(zhì)形成細(xì)胞和成纖維細(xì)胞等產(chǎn)生，并在胸腺中高表達(dá)，對T細(xì)胞的發(fā)育、遷移和成熟T細(xì)胞的激活起重要作用。CCL22和CCL17同屬于CC型趨化因子家族，二者具有高度同源性，具有共同的受體分子CCR4，都可以有效趨化CCR4表達(dá)陽性的細(xì)胞。
Figure 1. CCL17二聚體結(jié)構(gòu)，來源于PDB：1NR4。球體部分為G7T突變位置，綠色部分為二硫鍵位置。
來源：DOI: 10.1016/j.bbrep.2017.11.005
2. CCL17與疾病的關(guān)聯(lián)
2.1 心血管疾病
CCL17在心血管疾病中起著關(guān)鍵作用，尤其是在年齡相關(guān)和血管緊張素II (Ang II)誘導(dǎo)的病理性心臟重塑和心力衰竭中。研究發(fā)現(xiàn)，隨著年齡的增長，血清中CCL17水平顯著增加，并與心臟功能障礙相關(guān)。在動(dòng)物實(shí)驗(yàn)中，CCL17基因敲除小鼠顯示出對年齡和Ang II誘導(dǎo)的心臟肥大和纖維化的抑制作用，并伴隨著T細(xì)胞亞群的可塑性和分化 [1]。此外，使用抗CCL17中和抗體的治療也顯著抑制了Ang II誘導(dǎo)的病理性心臟重塑 [2]。這些發(fā)現(xiàn)揭示了CCL17作為一種新的治療靶點(diǎn)的潛力，可用于年齡相關(guān)和Ang II誘導(dǎo)的病理性心臟肥大和心力衰竭。
2.2 炎癥與自身免疫性疾病
趨化因子受體CCR4是CCL17的高親和力受體，CCL17在炎癥中的作用主要體現(xiàn)在其通過與CCR4結(jié)合，參與調(diào)控炎癥反應(yīng)和炎癥性疼痛。在炎癥模型中，CCL17能夠促進(jìn)炎癥性T細(xì)胞的趨化和激活，尤其是在Th2型免疫反應(yīng)中 [3]。在骨關(guān)節(jié)炎模型中，CCL17基因敲除小鼠顯示出對疼痛和疾病發(fā)展的抵抗性，表明CCL17在炎癥性疼痛的發(fā)病機(jī)制中起著關(guān)鍵作用 [4]。此外，在炎癥性關(guān)節(jié)炎和腸道炎癥模型中，CCL17的缺乏也能夠減輕疾病癥狀，進(jìn)一步支持了CCL17在炎癥中的重要作用 [5][6]。
在自身免疫疾病中，CCL17同樣扮演著重要角色 [3]。在系統(tǒng)性紅斑狼瘡（SLE）中，CCL17的表達(dá)也有所增加，提示其可能參與SLE的免疫病理過程 [7][8]。此外，在多發(fā)性硬化癥（MS）的動(dòng)物模型實(shí)驗(yàn)性自身免疫性腦脊髓炎（EAE）中，CCL17基因敲除小鼠顯示出減輕的疾病癥狀 [9]。這些研究結(jié)果表明，CCL17在自身免疫疾病的發(fā)病機(jī)制中具有重要作用，并可能成為治療這些疾病的新靶點(diǎn)。
CCL17在過敏性哮喘中發(fā)揮著關(guān)鍵作用，它由樹突狀細(xì)胞（DCs）產(chǎn)生，能吸引Th2細(xì)胞到氣道，引發(fā)過敏性哮喘的炎癥反應(yīng)。NOD1刺激的樹突狀細(xì)胞在體內(nèi)能加重Th2肺部反應(yīng)，且這種作用以CCL17依賴性方式發(fā)生 [10]。通過人源化SCID小鼠模型的研究發(fā)現(xiàn)，阻斷CCR4（CCL17的受體）能顯著減少氣道炎癥和支氣管高反應(yīng)性，表明CCR4-CCL17軸在Th2細(xì)胞招募到氣道中起到關(guān)鍵作用 [11]。這些研究結(jié)果都暗示了CCL17可能是一個(gè)潛在的治療過敏性哮喘的靶點(diǎn)。
2.3 腫瘤及腫瘤微環(huán)境
CCL17在多種腫瘤細(xì)胞中高表達(dá)，能促進(jìn)腫瘤細(xì)胞增殖、遷移和侵襲。在肝細(xì)胞癌中，與M2型巨噬細(xì)胞共培養(yǎng)或用CCL17處理，可增強(qiáng)腫瘤細(xì)胞的這些惡性生物學(xué)行為，還能提升細(xì)胞干性，促進(jìn)腫瘤球形成，并上調(diào)腫瘤干細(xì)胞相關(guān)轉(zhuǎn)錄因子表達(dá)，助力腫瘤復(fù)發(fā)和轉(zhuǎn)移 [12]。此外，CCL17通過激活TGF-β1/Smad和Wnt/β-catenin信號通路，影響上皮-間質(zhì)轉(zhuǎn)化過程，進(jìn)一步加強(qiáng)腫瘤細(xì)胞的侵襲和轉(zhuǎn)移能力 [13]。
CCL17與多種免疫細(xì)胞浸潤相關(guān)。在胃癌和甲狀腺癌中，其高表達(dá)與Foxp3+調(diào)節(jié)性T細(xì)胞聚集有關(guān)，可能抑制抗腫瘤免疫 [13][14]。同時(shí)，CCR4-CCL17信號軸選擇性招募Th2細(xì)胞、Tregs、記憶T細(xì)胞至炎癥或腫瘤微環(huán)境，通過JAK/STAT6、PI3K/AKT通路激活免疫抑制程序。
3. 相關(guān)信號通路研究
| 信號通路/分子 | 作用描述 | 相關(guān)疾病/細(xì)胞類型 | 參考文獻(xiàn) |
|---|---|---|---|
| CCL17/CCR4 | 促進(jìn)腫瘤細(xì)胞遷移、侵襲、干性維持，調(diào)控免疫細(xì)胞遷移 | 多種腫瘤、干細(xì)胞 | 12, 15, 16, 17, 18 |
| ERK/PD-L1 | CCL17通過CCR4激活ERK/PD-L1信號，增強(qiáng)腫瘤細(xì)胞惡性行為 | 食管鱗癌 | 15 |
| mTORC1/mTORC2 | 乳酸誘導(dǎo)M2極化，M2分泌CCL17，CCL17/CCR4激活mTORC1促進(jìn)腫瘤侵襲 | 垂體腺瘤 | 16, 19 |
| Wnt/β-catenin、TGF-β1 | CCL17促進(jìn)腫瘤細(xì)胞EMT及干性，激活Wnt/β-catenin和TGF-β1信號 | 肝細(xì)胞癌 | 12 |
| STAT6/IRF4/JMJD3 | IL-4誘導(dǎo)CCL17表達(dá)依賴STAT6-IRF4-JMJD3通路，涉及表觀遺傳調(diào)控 | 單核細(xì)胞/巨噬細(xì)胞 | 7 |
| β-arrestin | CCL17激活CCR4主要招募β-arrestin而非G蛋白，提示其可能作為清道夫受體 | T細(xì)胞 | 20 |
4. 臨床意義與應(yīng)用前景
4.1 生物標(biāo)志物與預(yù)后預(yù)測
CCL17/CCL22高表達(dá)可預(yù)測頭頸鱗癌患者的免疫檢查點(diǎn)抑制劑療效及生存率 [19]，在鼻型NK/T細(xì)胞淋巴瘤、肝癌等疾病中也有潛在的診斷和預(yù)后價(jià)值 [12][18]。
4.2 靶向治療潛力
抗CCR4單抗可介導(dǎo)NK細(xì)胞殺傷腫瘤細(xì)胞，CCL17/CCR4軸成為多種腫瘤的新型靶向治療候選 [18][21]。
5. 相關(guān)產(chǎn)品推薦
華美生物提供CCL17相關(guān)高質(zhì)量重組蛋白和抗體，旨在幫助科研工作者進(jìn)行CCL17作用機(jī)制與臨床轉(zhuǎn)化方向的研究：
● CCL17重組蛋白
Recombinant Human C-C motif chemokine 17 (CCL17) (Active); CSB-MP856406HU
Recombinant Macaca mulatta C-C motif chemokine 17 (CCL17) (Active); CSB-MP811562MOW
Recombinant Mouse C-C motif chemokine 17 (Ccl17) (Active); CSB-MP6512MO
● CCL17重組抗體
CCL17 Recombinant Monoclonal Antibody; CSB-RA856406MA1HU
Activity: Measured by its binding ability in a functional ELISA. Immobilized Anti-CCL17 recombinant antibody at 2 μg/mL can bind Human CCL17 protein (CSB-MP856406HU). The EC50 is 2.403-2.741 ng/mL.
● CCL17(TRAC) ELISA試劑盒
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