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(duì)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(yáng)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(zhǎng)，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(duì)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(duì)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(hào)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(rùn)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(hào)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(hào)通路研究
| 信號(hào)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(hào)，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(hào) | 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(cè)
CCL17/CCL22高表達(dá)可預(yù)測(cè)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
參考文獻(xiàn)：
[1] Zhang, Y., Ye, Y., Tang, X., Wang, H., Tanaka, T., Tian, R., Yang, X., Wang, L., Xiao, Y., Hu, X., Jin, Y., Pang, H., Du, T., Liu, H., Sun, L., Xiao, S., Dong, R., Ferrucci, L., Tian, Z., & Zhang, S. (2022). CCL17 acts as a novel therapeutic target in pathological cardiac hypertrophy and heart failure. The Journal of Experimental Medicine, 219(8).
[2] Zhang, Y., Tang, X., Wang, Z., Wang, L., Chen, Z., Qian, J. Y., Tian, Z., & Zhang, S. Y. (2023). The chemokine CCL17 is a novel therapeutic target for cardiovascular aging. Signal transduction and targeted therapy, 8(1), 157.
[3] Lupancu, T.J., Eivazitork, M., Hamilton, J.A., Achuthan, A.A. and Lee, K.M.-C. (2023), CCL17/TARC in autoimmunity and inflammation—not just a T-cell chemokine. Immunol Cell Biol, 101: 600-609.
[4] Lee, M.-C., Saleh, R., Achuthan, A., Fleetwood, A. J., F?rster, I., Hamilton, J. A., & Cook, A. D. (2018). CCL17 blockade as a therapy for osteoarthritis pain and disease. Arthritis Research & Therapy, 20(1), 62.
[5] Heiseke, A. F., Faul, A. C., Lehr, H., F?rster, I., Schmid, R. M., Krug, A. B., & Reindl, W. (2011). CCL17 Promotes Intestinal Inflammation in Mice and Counteracts Regulatory T Cell–Mediated Protection From Colitis. Gastroenterology, 142(2), 335–345.
[6] Achuthan, A., Cook, A. D., Kevin M.-C. Lee, Saleh, R., Hsu Wei Khiew, Melody Wei-Ning Chang, Louis, C., Fleetwood, A. J., Lacey, D., Anne Deen Christensen, Frye, A. T., Pui Yeng Lam, Kusano, H., Nomura, K., Steiner, N., F?rster, I., Nutt, S. L., Olshansky, M., Turner, S. J., & Hamilton, J. A. (2016). Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation. Journal of Clinical Investigation, 126(9), 3453–3466.
[7] Hsu, A. T., Lupancu, T. J., Lee, M.-C., Fleetwood, A. J., Cook, A. D., Hamilton, J. A., & Achuthan, A. (2018). Epigenetic and transcriptional regulation of IL4-induced CCL17 production in human monocytes and murine macrophages. Journal of Biological Chemistry, 293(29), 11415–11423.
[8] T R D J Radstake. (2004). Increased expression of CCL18, CCL19, and CCL17 by dendritic cells from patients with rheumatoid arthritis, and regulation by Fc gamma receptors. Annals of the Rheumatic Diseases, 64(3), 359–367.
[9] Dhaiban, S., Al-Ani, M., Elemam, N. M., & Maghazachi, A. A. (2020). Targeting Chemokines and Chemokine Receptors in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis. Journal of Inflammation Research, Volume 13, 619–633.
[10] Yahia, S. A., Imane Azzaoui, Laetitia Everaere, Vorng, H., Cécile Chenivesse, Philippe Marquillies, Duez, C., Delacre, M., Grandjean, T., Balsamelli, J., d’Andon, M. F., Fan, Y., Coline Ple, Werts, C., Ivo Gomperts Boneca, Wallaert, B., Mathias Chamaillard, & Tsicopoulos, A. (2014). CCL17 Production by Dendritic Cells Is Required for NOD1-mediated Exacerbation of Allergic Asthma. American Journal of Respiratory and Critical Care Medicine, 189(8), 899–908.
[11] Perros, F., Hoogsteden, H. C., Coyle, A. J., Lambrecht, B. N., & Hammad, H. (2009). Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation. Allergy, 64(7), 995–1002.
[12] Zhu, F., Li, X., Chen, S., Zeng, Q., Zhao, Y., & Luo, F. (2016). Tumor-associated macrophage or chemokine ligand CCL17 positively regulates the tumorigenesis of hepatocellular carcinoma. Medical Oncology, 33(2).
[13] Mizukami, Y., Kono, K., Kawaguchi, Y., Akaike, H., Kamimura, K., Sugai, H., & Fujii, H. (2008). CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer. International Journal of Cancer, 122(10), 2286–2293.
[14] Gu, X., Chen, B., Zhang, S., Zhai, X., Hu, Y., & Ye, H. (2024). The expression of CCL17 and potential prognostic value on tumor immunity in thyroid carcinoma based on bioinformatics analysis. Scientific Reports, 14(1).
[15] Jin, C., Lu, L., Gao, J., & Chen, L. (2024). M2-like Macrophages-derived CCL17 Promotes Esophageal Squamous Cell Carcinoma Metastasis and Stemness via Activating CCR4-mediated ERK/PD-L1 Pathway.. Current molecular medicine.
[16] Zhang, A., Xu, Y., Xu, H., Ren, J., Meng, T., Ni, Y., Zhu, Q., Zhang, W., Pan, Y., Jin, J., Bi, Y., Wu, Z., Lin, S., & Lou, M. (2021). Lactate-induced M2 polarization of tumor-associated macrophages promotes the invasion of pituitary adenoma by secreting CCL17. Theranostics, 11, 3839 - 3852.
[17] Konno, K., Sasaki, T., Kulkeaw, K., & Sugiyama, D. (2020). Paracrine CCL17 and CCL22 signaling regulates hematopoietic stem/progenitor cell migration and retention in mouse fetal liver.. Biochemical and biophysical research communications.
[18] Kumai, T., Nagato, T., Kobayashi, H., Komabayashi, Y., Ueda, S., Kishibe, K., Ohkuri, T., Takahara, M., Celis, E., & Harabuchi, Y. (2015). CCL17 and CCL22/CCR4 signaling is a strong candidate for novel targeted therapy against nasal natural killer/T-cell lymphoma. Cancer Immunology, Immunotherapy, 64, 697-705.
[19] Zhou, W., Zhang, X., Feng, Y., Zhang, Y., & Liu, Z. (2022). The CC ligand chemokine family members CCL17/CCL22 predict the survival and response to immune checkpoint blockade therapy of patients with head and neck squamous cell carcinoma.. Current problems in cancer, 46 6, 100896 .
[20] Lim, H., Lane, J., Canals, M., & Stone, M. (2021). Systematic Assessment of Chemokine Signaling at Chemokine Receptors CCR4, CCR7 and CCR10. International Journal of Molecular Sciences, 22.
[21] Goenka, A., Khan, F., Verma, B., Sinha, P., Dmello, C., Jogalekar, M., Gangadaran, P., & Ahn, B. (2023). Tumor microenvironment signaling and therapeutics in cancer progression. Cancer Communications, 43, 525 - 561.
