CCL28在心脏移植排斥反应中的潜在作用
The Potential Role of CCL28 in Cardiac Allograft Rejection
摘要: 心脏移植是终末期心力衰竭的有效治疗手段,但术后排斥反应严重制约移植物长期存活。趋化因子CCL28作为黏膜免疫的关键调节因子,通过其受体CCR3和CCR10发挥多样的免疫调控功能。近年来研究表明,CCL28在中性粒细胞募集和活化中起重要作用,而中性粒细胞及其释放的中性粒细胞胞外陷阱(NETs)在移植排斥反应中的作用日益受到关注。本文系统综述CCL28的生物学特性、中性粒细胞在免疫应答中的功能、NETosis的形成机制及其在移植排斥中的潜在作用,并探讨可能存在的CCL28/CCR3/NETosis轴在心脏移植排斥中的潜在机制,以期为临床防治心脏移植排斥提供新的理论依据和治疗靶点。
Abstract: Heart transplantation is an effective therapeutic approach for end-stage heart failure; however, post-transplant rejection remains a major obstacle to long-term graft survival. The chemokine CCL28, a key regulator of mucosal immunity, exerts diverse immunomodulatory functions through its receptors CCR3 and CCR10. Recent studies have highlighted the critical role of CCL28 in neutrophil recruitment and activation, while the involvement of neutrophils and neutrophil extracellular traps (NETs) in transplant rejection has garnered increasing attention. This article systematically reviews the biological characteristics of CCL28, the functions of neutrophils in immune responses, the mechanisms of NETosis, and their potential roles in transplant rejection. Furthermore, we explore the possible involvement of the CCL28/CCR3/NETosis axis in cardiac allograft rejection, aiming to provide new theoretical insights and therapeutic targets for the clinical management of cardiac transplant rejection.
文章引用:孙宇鹏, 董爱强. CCL28在心脏移植排斥反应中的潜在作用[J]. 临床医学进展, 2026, 16(4): 2438-2450. https://doi.org/10.12677/acm.2026.1641494

参考文献

[1] Barnard, C.N. (1967) The Operation. A Human Cardiac Transplant: An Interim Report of a Successful Operation Performed at Groote Schuur Hospital, Cape Town. South African Medical Journal, 41, 1271-1274.
[2] Khush, K.K., Cherikh, W.S., Chambers, D.C., Goldfarb, S., Hayes, D., Kucheryavaya, A.Y., et al. (2018) The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-Fifth Adult Heart Transplantation Report—2018. The Journal of Heart and Lung Transplantation, 37, 1155-1168. [Google Scholar] [CrossRef] [PubMed]
[3] Madill-Thomsen, K.S., Guembes, L., Mackova, M., et al. (2025) Defining the Relationships among Four Tests for Assessing Antibody-Mediated Rejection in Heart Transplants. Journal of Heart and Lung Transplantation, 44, 1-14.
[4] Lund, L.H., Edwards, L.B., Kucheryavaya, A.Y., Benden, C., Dipchand, A.I., Goldfarb, S., et al. (2015) The Registry of the International Society for Heart and Lung Transplantation: Thirty-Second Official Adult Heart Transplantation Report—2015; Focus Theme: Early Graft Failure. The Journal of Heart and Lung Transplantation, 34, 1244-1254. [Google Scholar] [CrossRef] [PubMed]
[5] Pan, J., Kunkel, E.J., Gosslar, U., Lazarus, N., Langdon, P., Broadwell, K., et al. (2000) Cutting Edge: A Novel Chemokine Ligand for CCR10 and CCR3 Expressed by Epithelial Cells in Mucosal Tissues. The Journal of Immunology, 165, 2943-2949. [Google Scholar] [CrossRef] [PubMed]
[6] Mohan, T., Deng, L. and Wang, B. (2017) CCL28 Chemokine: An Anchoring Point Bridging Innate and Adaptive Immunity. International Immunopharmacology, 51, 165-170. [Google Scholar] [CrossRef] [PubMed]
[7] Danilova, E., Skrindo, I., Gran, E., Hales, B.J., Smith, W.A., Jahnsen, J., et al. (2015) A Role for CCL28-CCR3 in T-Cell Homing to the Human Upper Airway Mucosa. Mucosal Immunology, 8, 107-114. [Google Scholar] [CrossRef] [PubMed]
[8] Walker, G.T., Perez-Lopez, A., Silva, S., Lee, M.H., Bjånes, E., Dillon, N., et al. (2024) CCL28 Modulates Neutrophil Responses during Infection with Mucosal Pathogens. eLife, 13, e78206. [Google Scholar] [CrossRef] [PubMed]
[9] Hirao, H., Nakamura, K. and Kupiec-Weglinski, J.W. (2022) Liver Ischaemia-Reperfusion Injury: A New Understanding of the Role of Innate Immunity. Nature Reviews Gastroenterology & Hepatology, 19, 239-256. [Google Scholar] [CrossRef] [PubMed]
[10] Sayah, D.M., Mallavia, B., Liu, F., Ortiz-Muñoz, G., Caudrillier, A., DerHovanessian, A., et al. (2015) Neutrophil Extracellular Traps Are Pathogenic in Primary Graft Dysfunction after Lung Transplantation. American Journal of Respiratory and Critical Care Medicine, 191, 455-463. [Google Scholar] [CrossRef] [PubMed]
[11] Wang, W., Soto, H., Oldham, E.R., Buchanan, M.E., Homey, B., Catron, D., et al. (2000) Identification of a Novel Chemokine (CCL28), Which Binds CCR10 (GPR2). Journal of Biological Chemistry, 275, 22313-22323. [Google Scholar] [CrossRef] [PubMed]
[12] Meurens, F., Berri, M., Whale, J., Dybvig, T., Strom, S., Thompson, D., et al. (2006) Expression of TECK/CCL25 and MEC/CCL28 Chemokines and Their Respective Receptors CCR9 and CCR10 in Porcine Mucosal Tissues. Veterinary Immunology and Immunopathology, 113, 313-327. [Google Scholar] [CrossRef] [PubMed]
[13] Hieshima, K., Ohtani, H., Shibano, M., Izawa, D., Nakayama, T., Kawasaki, Y., et al. (2003) CCL28 Has Dual Roles in Mucosal Immunity as a Chemokine with Broad-Spectrum Antimicrobial Activity. The Journal of Immunology, 170, 1452-1461. [Google Scholar] [CrossRef] [PubMed]
[14] Willems, L.I. and IJzerman, A.P. (2010) Small Molecule Antagonists for Chemokine CCR3 Receptors. Medicinal Research Reviews, 30, 778-817. [Google Scholar] [CrossRef] [PubMed]
[15] Homey, B., Wang, W., Soto, H., Buchanan, M.E., Wiesenborn, A., Catron, D., et al. (2000) Cutting Edge: The Orphan Chemokine Receptor G Protein-Coupled Receptor-2 (GPR-2, CCR10) Binds the Skin-Associated Chemokine CCL27 (CTACK/ALP/ILC). The Journal of Immunology, 164, 3465-3470. [Google Scholar] [CrossRef] [PubMed]
[16] Lazarus, N.H., Kunkel, E.J., Johnston, B., Wilson, E., Youngman, K.R. and Butcher, E.C. (2003) A Common Mucosal Chemokine (Mucosae-Associated Epithelial Chemokine/CCL28) Selectively Attracts Iga Plasmablasts. The Journal of Immunology, 170, 3799-3805. [Google Scholar] [CrossRef] [PubMed]
[17] Wilson, E. and Butcher, E.C. (2004) CCL28 Controls Immunoglobulin (Ig)a Plasma Cell Accumulation in the Lactating Mammary Gland and Iga Antibody Transfer to the Neonate. The Journal of Experimental Medicine, 200, 805-809. [Google Scholar] [CrossRef] [PubMed]
[18] Höchstetter, R., Dobos, G., Kimmig, D., Dulkys, Y., Kapp, A. and Elsner, J. (2000) The CC Chemokine Receptor 3 CCR3 Is Functionally Expressed on Eosinophils but Not on Neutrophils. European Journal of Immunology, 30, 2759-2764. [Google Scholar] [CrossRef] [PubMed]
[19] Hartl, D., Krauss-Etschmann, S., Koller, B., Hordijk, P.L., Kuijpers, T.W., Hoffmann, F., et al. (2008) Infiltrated Neutrophils Acquire Novel Chemokine Receptor Expression and Chemokine Responsiveness in Chronic Inflammatory Lung Diseases. The Journal of Immunology, 181, 8053-8067. [Google Scholar] [CrossRef] [PubMed]
[20] O’Gorman, M.T., Jatoi, N.A., Lane, S.J. and Mahon, B.P. (2005) Il-1β and TNF-Α Induce Increased Expression of CCL28 by Airway Epithelial Cells via an NFκB-Dependent Pathway. Cellular Immunology, 238, 87-96. [Google Scholar] [CrossRef] [PubMed]
[21] Ogawa, H., Iimura, M., Eckmann, L. and Kagnoff, M.F. (2004) Regulated Production of the Chemokine CCL28 in Human Colon Epithelium. American Journal of Physiology-Gastrointestinal and Liver Physiology, 287, G1062-G1069. [Google Scholar] [CrossRef] [PubMed]
[22] Facciabene, A., Peng, X., Hagemann, I.S., Balint, K., Barchetti, A., Wang, L., et al. (2011) Tumour Hypoxia Promotes Tolerance and Angiogenesis via CCL28 and Treg Cells. Nature, 475, 226-230. [Google Scholar] [CrossRef] [PubMed]
[23] Huang, G., Tao, L., Shen, S. and Chen, L. (2016) Hypoxia Induced CCL28 Promotes Angiogenesis in Lung Adenocarcinoma by Targeting CCR3 on Endothelial Cells. Scientific Reports, 6, Article No. 27152. [Google Scholar] [CrossRef] [PubMed]
[24] Yang, K., Chen, H., Lyu, Y., Wei, W., Wei, X., Ling, Y., et al. (2025) CCL28 Contributes to Angiogenesis and Cardiac Repair through CCR10+ Endothelial Cells after Myocardial Infarction in Male Mice. Nature Communications, 16, Article No. 9262. [Google Scholar] [CrossRef
[25] Eksteen, B., Miles, A., Curbishley, S.M., Tselepis, C., Grant, A.J., Walker, L.S.K., et al. (2006) Epithelial Inflammation Is Associated with CCL28 Production and the Recruitment of Regulatory T Cells Expressing Ccr10. The Journal of Immunology, 177, 593-603. [Google Scholar] [CrossRef] [PubMed]
[26] Hansson, M., Hermansson, M., Svensson, H., Elfvin, A., Hansson, L., Johnsson, E., et al. (2008) CCL28 Is Increased in Human helicobacter Pylori-Induced Gastritis and Mediates Recruitment of Gastric Immunoglobulin A-Secreting Cells. Infection and Immunity, 76, 3304-3311. [Google Scholar] [CrossRef] [PubMed]
[27] Rudd, J.M., Pulavendran, S., Ashar, H.K., Ritchey, J.W., Snider, T.A., Malayer, J.R., et al. (2019) Neutrophils Induce a Novel Chemokine Receptors Repertoire during Influenza Pneumonia. Frontiers in Cellular and Infection Microbiology, 9, Article ID: 108. [Google Scholar] [CrossRef] [PubMed]
[28] Spencer, L.A., Melo, R.C.N., Perez, S.A.C., Bafford, S.P., Dvorak, A.M. and Weller, P.F. (2006) Cytokine Receptor-Mediated Trafficking of Preformed IL-4 in Eosinophils Identifies an Innate Immune Mechanism of Cytokine Secretion. Proceedings of the National Academy of Sciences, 103, 3333-3338. [Google Scholar] [CrossRef] [PubMed]
[29] Brinkmann, V., Reichard, U., Goosmann, C., Fauler, B., Uhlemann, Y., Weiss, D.S., et al. (2004) Neutrophil Extracellular Traps Kill Bacteria. Science, 303, 1532-1535. [Google Scholar] [CrossRef] [PubMed]
[30] Dwyer, M., Shan, Q., D’Ortona, S., Maurer, R., Mitchell, R., Olesen, H., et al. (2014) Cystic Fibrosis Sputum DNA Has Netosis Characteristics and Neutrophil Extracellular Trap Release Is Regulated by Macrophage Migration-Inhibitory Factor. Journal of Innate Immunity, 6, 765-779. [Google Scholar] [CrossRef] [PubMed]
[31] Papayannopoulos, V. (2018) Neutrophil Extracellular Traps in Immunity and Disease. Nature Reviews Immunology, 18, 134-147. [Google Scholar] [CrossRef] [PubMed]
[32] Papayannopoulos, V., Metzler, K.D., Hakkim, A. and Zychlinsky, A. (2010) Neutrophil Elastase and Myeloperoxidase Regulate the Formation of Neutrophil Extracellular Traps. Journal of Cell Biology, 191, 677-691. [Google Scholar] [CrossRef] [PubMed]
[33] Bianchi, M., Hakkim, A., Brinkmann, V., Siler, U., Seger, R.A., Zychlinsky, A., et al. (2009) Restoration of NET Formation by Gene Therapy in CGD Controls Aspergillosis. Blood, 114, 2619-2622. [Google Scholar] [CrossRef] [PubMed]
[34] Wang, Y., Wysocka, J., Sayegh, J., Lee, Y., Perlin, J.R., Leonelli, L., et al. (2004) Human PAD4 Regulates Histone Arginine Methylation Levels via Demethylimination. Science, 306, 279-283. [Google Scholar] [CrossRef] [PubMed]
[35] Li, P., Li, M., Lindberg, M.R., Kennett, M.J., Xiong, N. and Wang, Y. (2010) PAD4 Is Essential for Antibacterial Innate Immunity Mediated by Neutrophil Extracellular Traps. Journal of Experimental Medicine, 207, 1853-1862. [Google Scholar] [CrossRef] [PubMed]
[36] Hosseinzadeh, A., Thompson, P.R., Segal, B.H. and Urban, C.F. (2016) Nicotine Induces Neutrophil Extracellular Traps. Journal of Leukocyte Biology, 100, 1105-1112. [Google Scholar] [CrossRef] [PubMed]
[37] Pilsczek, F.H., Salina, D., Poon, K.K.H., Fahey, C., Yipp, B.G., Sibley, C.D., et al. (2010) A Novel Mechanism of Rapid Nuclear Neutrophil Extracellular Trap Formation in Response to Staphylococcus aureus. The Journal of Immunology, 185, 7413-7425. [Google Scholar] [CrossRef] [PubMed]
[38] Yipp, B.G., Petri, B., Salina, D., Jenne, C.N., Scott, B.N.V., Zbytnuik, L.D., et al. (2012) Infection-Induced Netosis Is a Dynamic Process Involving Neutrophil Multitasking in Vivo. Nature Medicine, 18, 1386-1393. [Google Scholar] [CrossRef] [PubMed]
[39] Douda, D.N., Khan, M.A., Grasemann, H. and Palaniyar, N. (2015) SK3 Channel and Mitochondrial ROS Mediate NADPH Oxidase-Independent Netosis Induced by Calcium Influx. Proceedings of the National Academy of Sciences, 112, 2817-2822. [Google Scholar] [CrossRef] [PubMed]
[40] Urban, C.F., Reichard, U., Brinkmann, V. and Zychlinsky, A. (2006) Neutrophil Extracellular Traps Capture and Kill Candida Albicans Yeast and Hyphal Forms. Cellular Microbiology, 8, 668-676. [Google Scholar] [CrossRef] [PubMed]
[41] Saffarzadeh, M., Juenemann, C., Queisser, M.A., Lochnit, G., Barreto, G., Galuska, S.P., et al. (2012) Neutrophil Extracellular Traps Directly Induce Epithelial and Endothelial Cell Death: A Predominant Role of Histones. PLOS ONE, 7, e32366. [Google Scholar] [CrossRef] [PubMed]
[42] Xu, J., Zhang, X., Pelayo, R., Monestier, M., Ammollo, C.T., Semeraro, F., et al. (2009) Extracellular Histones Are Major Mediators of Death in Sepsis. Nature Medicine, 15, 1318-1321. [Google Scholar] [CrossRef] [PubMed]
[43] Fuchs, T.A., Brill, A., Duerschmied, D., Schatzberg, D., Monestier, M., Myers, D.D., et al. (2010) Extracellular DNA Traps Promote Thrombosis. Proceedings of the National Academy of Sciences, 107, 15880-15885. [Google Scholar] [CrossRef] [PubMed]
[44] Martinod, K., Demers, M., Fuchs, T.A., Wong, S.L., Brill, A., Gallant, M., et al. (2013) Neutrophil Histone Modification by Peptidylarginine Deiminase 4 Is Critical for Deep Vein Thrombosis in Mice. Proceedings of the National Academy of Sciences, 110, 8674-8679. [Google Scholar] [CrossRef] [PubMed]
[45] Kessenbrock, K., Krumbholz, M., Schönermarck, U., Back, W., Gross, W.L., Werb, Z., et al. (2009) Netting Neutrophils in Autoimmune Small-Vessel Vasculitis. Nature Medicine, 15, 623-625. [Google Scholar] [CrossRef] [PubMed]
[46] Lande, R., Ganguly, D., Facchinetti, V., Frasca, L., Conrad, C., Gregorio, J., et al. (2011) Neutrophils Activate Plasmacytoid Dendritic Cells by Releasing Self-DNA-Peptide Complexes in Systemic Lupus Erythematosus. Science Translational Medicine, 3, 73ra19. [Google Scholar] [CrossRef] [PubMed]
[47] Cools-Lartigue, J., Spicer, J., McDonald, B., Gowing, S., Chow, S., Giannias, B., et al. (2013) Neutrophil Extracellular Traps Sequester Circulating Tumor Cells and Promote Metastasis. Journal of Clinical Investigation, 123, 3446-3458. [Google Scholar] [CrossRef] [PubMed]
[48] Tohme, S., Yazdani, H.O., Al-Khafaji, A.B., Chidi, A.P., Loughran, P., Mowen, K., et al. (2016) Neutrophil Extracellular Traps Promote the Development and Progression of Liver Metastases after Surgical Stress. Cancer Research, 76, 1367-1380. [Google Scholar] [CrossRef] [PubMed]
[49] Yang, L., Liu, Q., Zhang, X., Liu, X., Zhou, B., Chen, J., et al. (2020) DNA of Neutrophil Extracellular Traps Promotes Cancer Metastasis via Ccdc25. Nature, 583, 133-138. [Google Scholar] [CrossRef] [PubMed]
[50] Takesue, S., Ohuchida, K., Shinkawa, T., Otsubo, Y., Matsumoto, S., Sagara, A., et al. (2020) Neutrophil Extracellular Traps Promote Liver Micrometastasis in Pancreatic Ductal Adenocarcinoma via the Activation of Cancerassociated Fibroblasts. International Journal of Oncology, 56, 596-605. [Google Scholar] [CrossRef] [PubMed]
[51] Li, C., Chen, T., Liu, J., Wang, Y., Zhang, C., Guo, L., et al. (2023) Fgf19‐Induced Inflammatory CAF Promoted Neutrophil Extracellular Trap Formation in the Liver Metastasis of Colorectal Cancer. Advanced Science, 10, e2302613. [Google Scholar] [CrossRef] [PubMed]
[52] Li, J., Han, Z., Zhu, Z. and Wei, L. (2023) LncRNA H19 Aggravates Primary Graft Dysfunction after Lung Transplantation via KLF5-Mediated Activation of CCL28. American Journal of Transplantation, 23, 1536-1550. [Google Scholar] [CrossRef] [PubMed]
[53] Chen, J., Xu, C., Yang, K., Gao, R., Cao, Y., Liang, L., et al. (2023) Inhibition of ALKBH5 Attenuates I/R-Induced Renal Injury in Male Mice by Promoting CCL28 M6a Modification and Increasing Treg Recruitment. Nature Communications, 14, Article No. 1161. [Google Scholar] [CrossRef] [PubMed]
[54] Li, W., Feng, G., Gauthier, J.M., Lokshina, I., Higashikubo, R., Evans, S., et al. (2019) Ferroptotic Cell Death and TLR4/Trif Signaling Initiate Neutrophil Recruitment after Heart Transplantation. Journal of Clinical Investigation, 129, 2293-2304. [Google Scholar] [CrossRef] [PubMed]
[55] Hirao, H., Kojima, H., Dery, K.J., Nakamura, K., Kadono, K., Zhai, Y., et al. (2023) Neutrophil CEACAM1 Determines Susceptibility to Netosis by Regulating the S1PR2/S1PR3 Axis in Liver Transplantation. Journal of Clinical Investigation, 133, e162940. [Google Scholar] [CrossRef] [PubMed]
[56] Chen, Z., Haus, J.M., DiPietro, L.A., Koh, T.J. and Minshall, R.D. (2023) Neutralization of Excessive CCL28 Improves Wound Healing in Diabetic Mice. Frontiers in Pharmacology, 14, Article ID: 1087924. [Google Scholar] [CrossRef] [PubMed]
[57] Knight, J.S., Subramanian, V., O’Dell, A.A., Yalavarthi, S., Zhao, W., Smith, C.K., et al. (2015) Peptidylarginine Deiminase Inhibition Disrupts NET Formation and Protects against Kidney, Skin and Vascular Disease in Lupus-Prone MRL/LPR Mice. Annals of the Rheumatic Diseases, 74, 2199-2206. [Google Scholar] [CrossRef] [PubMed]