Carvacrol ameliorates skin allograft rejection through modulating macrophage polarization by activating the Wnt signalling pathway
Wentao Zhao
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Contribution: Conceptualization, Data curation, Investigation, Software, Validation, Visualization, Writing - original draft, Writing - review & editing
Search for more papers by this authorHong Tang
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Contribution: Software, Validation, Visualization, Writing - original draft, Writing - review & editing
Search for more papers by this authorZhi Liang
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Contribution: Conceptualization, Data curation
Search for more papers by this authorNing Wang
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Contribution: Methodology
Search for more papers by this authorRuiqi Sun
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Contribution: Methodology
Search for more papers by this authorRong Su
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
Contribution: Methodology
Search for more papers by this authorZhentao Yang
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Contribution: Methodology
Search for more papers by this authorKe Zhou
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Contribution: Methodology
Search for more papers by this authorYiyang Peng
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
Contribution: Methodology
Search for more papers by this authorCorresponding Author
Shusen Zheng
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China
Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, China
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
Correspondence
Haiyang Xie and Shusen Zheng, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China.
Email: [email protected] and [email protected]
Contribution: Project administration, Resources
Search for more papers by this authorCorresponding Author
Haiyang Xie
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China
Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, China
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
Correspondence
Haiyang Xie and Shusen Zheng, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China.
Email: [email protected] and [email protected]
Contribution: Formal analysis, Funding acquisition, Project administration, Supervision
Search for more papers by this authorWentao Zhao
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Contribution: Conceptualization, Data curation, Investigation, Software, Validation, Visualization, Writing - original draft, Writing - review & editing
Search for more papers by this authorHong Tang
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Contribution: Software, Validation, Visualization, Writing - original draft, Writing - review & editing
Search for more papers by this authorZhi Liang
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Contribution: Conceptualization, Data curation
Search for more papers by this authorNing Wang
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Contribution: Methodology
Search for more papers by this authorRuiqi Sun
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Contribution: Methodology
Search for more papers by this authorRong Su
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
Contribution: Methodology
Search for more papers by this authorZhentao Yang
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Contribution: Methodology
Search for more papers by this authorKe Zhou
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Contribution: Methodology
Search for more papers by this authorYiyang Peng
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
Contribution: Methodology
Search for more papers by this authorCorresponding Author
Shusen Zheng
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China
Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, China
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
Correspondence
Haiyang Xie and Shusen Zheng, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China.
Email: [email protected] and [email protected]
Contribution: Project administration, Resources
Search for more papers by this authorCorresponding Author
Haiyang Xie
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China
Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, China
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
Correspondence
Haiyang Xie and Shusen Zheng, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China.
Email: [email protected] and [email protected]
Contribution: Formal analysis, Funding acquisition, Project administration, Supervision
Search for more papers by this authorWentao Zhao and Hong Tang contributed equally to this work.
Abstract
Post-transplantation immune rejection remains an important factor for transplant patients. However, conventional immunosuppressants are associated with substantial adverse effects. Natural immunosuppressants present a promising alternative to conventional counterparts, boasting exceptional biological activity, minimal toxicity and reduced side effects. We identified carvacrol as a prospective immunosuppressive agent following T cell proliferation experiment and validated carvacrol's immunosuppressive efficacy in the murine allogeneic skin graft model. T cell proliferation assay was used to screen natural small molecule compounds and the immunosuppressive effect of compounds was evaluated in MHC-mismatched murine allogeneic skin graft model. H&E and immunohistochemical staining were applied to evaluate the pathological grade. Furthermore, flow cytometry was uitlized to analyse the immunophenotype changes of immune cells. Western blotting and q-PCR were used to detect the expression of key molecules in macrophages. In vitro, carvacrol demonstrates significant inhibition of the proliferation of CD4+ T and CD8+ T cells. It notably reduces inflammatory factor expression within the allografts, suppresses T cell differentiation toward Th1 phenotype and expansion. Furthermore, carvacrol prominently hinders M1-type macrophages polarization by activating Wnt signaling. Notably, the anti-rejection efficacy of carvacrol was significantly weakened upon the removal of macrophages in mice using chlorophosphate liposomes. Carvacrol could significantly inhibit T cell proliferation, alleviate graft rejection and has outstanding toxicological safety. The molecular mechanism of the anti-rejection effect of carvacrol is closely related to its mediating activation of macrophage Wnt pathway, inhibiting M1 polarization and inducing T cell differentiation.
CONFLICT OF INTEREST STATEMENT
We declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Open Research
DATA AVAILABILITY STATEMENT
Data will be made available on request.
Supporting Information
| Filename | Description |
|---|---|
| ptr8282-sup-0001-AppendixS1.docxWord 2007 document , 10.1 MB | Appendix S1. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- Abaricia, J. O., Shah, A. H., Chaubal, M., Hotchkiss, K. M., & Olivares-Navarrete, R. (2020). Wnt signaling modulates macrophage polarization and is regulated by biomaterial surface properties. Biomaterials, 243, 119920. https://doi.org/10.1016/j.biomaterials.2020.119920
- Bishawi, M., Bowles, D., Pla, M. M., Oakes, F., Chiang, Y., Schroder, J., Milano, C., & Glass, C. (2021). PD-1 and PD-L1 expression in cardiac transplantation. Cardiovascular Pathology, 54, 107331. https://doi.org/10.1016/j.carpath.2021.107331
- Borges, T. J., Murakami, N., Lape, I. T., Gassen, R. B., Liu, K., Cai, S., Daccache, J., Safa, K., Shimizu, T., Ohori, S., Paterson, A. M., Cravedi, P., Azzi, J., Sage, P. T., Sharpe, A. H., Li, X. C., & Riella, L. V. (2021). Overexpression of PD-1 on T cells promotes tolerance in cardiac transplantation via ICOS-dependent mechanisms. JCI Insight, 6(24), e142909. https://doi.org/10.1172/jci.insight.142909
- Busch, D. H., Frassle, S. P., Sommermeyer, D., Buchholz, V. R., & Riddell, S. R. (2016). Role of memory T cell subsets for adoptive immunotherapy. Seminars in Immunology, 28(1), 28–34. https://doi.org/10.1016/j.smim.2016.02.001
- Carnel, N., Lancia, H. H., Guinier, C., & Benichou, G. (2023). Pathways of antigen recognition by T cells in allograft rejection. Transplantation, 107(4), 827–837. https://doi.org/10.1097/TP.0000000000004420
- Choy, J. C. (2010). Granzymes and perforin in solid organ transplant rejection. Cell Death and Differentiation, 17(4), 567–576. https://doi.org/10.1038/cdd.2009.161
- Cucak, H., Nielsen Fink, L., Hojgaard Pedersen, M., & Rosendahl, A. (2015). Enalapril treatment increases T cell number and promotes polarization towards M1-like macrophages locally in diabetic nephropathy. International Immunopharmacology, 25(1), 30–42. https://doi.org/10.1016/j.intimp.2015.01.003
- Dong, C. (2021). Cytokine regulation and function in T cells. Annual Review of Immunology, 39, 51–76. https://doi.org/10.1146/annurev-immunol-061020-053702
- Du, X., Que, W., Hu, X., Yu, X., Guo, W. Z., Zhang, S., & Li, X. K. (2021). Oridonin prolongs the survival of mouse cardiac allografts by attenuating the NF-kappaB/NLRP3 pathway. Frontiers in Immunology, 12, 719574. https://doi.org/10.3389/fimmu.2021.719574
- Edozie, F. C., Nova-Lamperti, E. A., Povoleri, G. A., Scotta, C., John, S., Lombardi, G., & Afzali, B. (2014). Regulatory T-cell therapy in the induction of transplant tolerance: The issue of subpopulations. Transplantation, 98(4), 370–379. https://doi.org/10.1097/TP.0000000000000243
- Ford, M. L. (2016). T cell cosignaling molecules in transplantation. Immunity, 44(5), 1020–1033. https://doi.org/10.1016/j.immuni.2016.04.012
- Fryer, J., Grant, D., Jiang, J., Metrakos, P., Ozcay, N., Ford, C., & Zhong, R. (1996). Influence of macrophage depletion on bacterial translocation and rejection in small bowel transplantation. Transplantation, 62(5), 553–559. https://doi.org/10.1097/00007890-199609150-00002
- Galluzzi, L., Humeau, J., Buque, A., Zitvogel, L., & Kroemer, G. (2020). Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nature Reviews. Clinical Oncology, 17(12), 725–741. https://doi.org/10.1038/s41571-020-0413-z
- Gandhi, G. R., Neta, M., Sathiyabama, R. G., Quintans, J. S. S., de Oliveira e Silva, A. M., Araújo, A. A. S., Narain, N., Júnior, L. J. Q., & Gurgel, R. Q. (2018). Flavonoids as Th1/Th2 cytokines immunomodulators: A systematic review of studies on animal models. Phytomedicine, 44, 74–84. https://doi.org/10.1016/j.phymed.2018.03.057
- Gholijani, N., & Amirghofran, Z. (2016). Effects of thymol and carvacrol on T-helper cell subset cytokines and their main transcription factors in ovalbumin-immunized mice. Journal of Immunotoxicology, 13(5), 729–737. https://doi.org/10.3109/1547691X.2016.1173134
- Gholijani, N., Gharagozloo, M., Farjadian, S., & Amirghofran, Z. (2016). Modulatory effects of thymol and carvacrol on inflammatory transcription factors in lipopolysaccharide-treated macrophages. Journal of Immunotoxicology, 13(2), 157–164. https://doi.org/10.3109/1547691X.2015.1029145
- Guimarães, A. G., Xavier, M. A., de Santana, M. T., Camargo, E. A., Santos, C. A., Brito, F. A., Barreto, E. O., Cavalcanti, S. C. H., Antoniolli, Â. R., Oliveira, R. C. M., & Quintans-Júnior, L. J. (2012). Carvacrol attenuates mechanical hypernociception and inflammatory response. Naunyn-Schmiedeberg's Archives of Pharmacology, 385(3), 253–263. https://doi.org/10.1007/s00210-011-0715-x
- Hou, N., Mai, Y., Qiu, X., Yuan, W., Li, Y., Luo, C., Liu, Y., Zhang, G., Zhao, G., & Luo, J. D. (2019). Carvacrol attenuates diabetic cardiomyopathy by modulating the PI3K/AKT/GLUT4 pathway in diabetic mice. Frontiers in Pharmacology, 10, 998. https://doi.org/10.3389/fphar.2019.00998
- Imran, M., Aslam, M., Alsagaby, S. A., Saeed, F., Ahmad, I., Afzaal, M., Arshad, M. U., Abdelgawad, M. A., el-Ghorab, A. H., Khames, A., Shariati, M. A., Ahmad, A., Hussain, M., Imran, A., & Islam, S. (2022). Therapeutic application of carvacrol: A comprehensive review. Food Science & Nutrition, 10(11), 3544–3561. https://doi.org/10.1002/fsn3.2994
- Jang, G. B., Hong, I. S., Kim, R. J., Lee, S. Y., Park, S. J., Lee, E. S., Park, J. H., Yun, C. H., Chung, J. U., Lee, K. J., Lee, H. Y., & Nam, J. S. (2015). Wnt/β-catenin small-molecule inhibitor CWP232228 preferentially inhibits the growth of breast cancer stem-like cells. Cancer Research, 75(8), 1691–1702. https://doi.org/10.1158/0008-5472.Can-14-2041
- Jenssen, T., & Hartmann, A. (2019). Post-transplant diabetes mellitus in patients with solid organ transplants. Nature Reviews. Endocrinology, 15(3), 172–188. https://doi.org/10.1038/s41574-018-0137-7
- Kasiske, B. L., de Mattos, A., Flechner, S. M., Gallon, L., Meier-Kriesche, H. U., Weir, M. R., & Wilkinson, A. (2008). Mammalian target of rapamycin inhibitor dyslipidemia in kidney transplant recipients. American Journal of Transplantation, 8(7), 1384–1392. https://doi.org/10.1111/j.1600-6143.2008.02272.x
- Keir, M. E., Butte, M. J., Freeman, G. J., & Sharpe, A. H. (2008). PD-1 and its ligands in tolerance and immunity. Annual Review of Immunology, 26, 677–704. https://doi.org/10.1146/annurev.immunol.26.021607.090331
- Li, Y., Xu, J. Z., Gu, C. X., Liu, G. L., & Tian, K. (2019). Carvacrol suppresses inflammatory responses in rheumatoid arthritis fibroblast-like synoviocytes. Journal of Cellular Biochemistry, 120(5), 8169–8176. https://doi.org/10.1002/jcb.28098
- Li, Z., Xu, X., Feng, X., & Murphy, P. M. (2016). The macrophage-depleting agent clodronate promotes durable hematopoietic chimerism and donor-specific skin allograft tolerance in mice. Scientific Reports, 6, 22143. https://doi.org/10.1038/srep22143
- Marino, J., Paster, J., & Benichou, G. (2016). Allorecognition by T lymphocytes and allograft rejection. Frontiers in Immunology, 7, 582. https://doi.org/10.3389/fimmu.2016.00582
- Nair, A. B., & Jacob, S. (2016). A simple practice guide for dose conversion between animals and human. Journal of Basic and Clinical Pharmacy, 7(2), 27–31. https://doi.org/10.4103/0976-0105.177703
- Panther, F., Strasen, J., Czolbe, M., Lazariotou, M., Burkard, N., Williams, T., Lange, V., Otto, C., & Ritter, O. (2011). Inhibition of nuclear translocation of calcineurin suppresses T-cell activation and prevents acute rejection of donor hearts. Transplantation, 91(6), 597–604. https://doi.org/10.1097/TP.0b013e3182090f67
- Pascual-Gil, S., & Epelman, S. (2018). Monocyte-derived macrophages: The missing link in organ transplantation. Immunity, 49(5), 783–785. https://doi.org/10.1016/j.immuni.2018.11.005
- Riaz, M., Al Kury, L. T., Atzaz, N., Alattar, A., Alshaman, R., Shah, F. A., & Li, S. (2022). Carvacrol alleviates hyperuricemia-induced oxidative stress and inflammation by modulating the NLRP3/NF-kappaB Pathwayt. Drug Design, Development and Therapy, 16, 1159–1170. https://doi.org/10.2147/DDDT.S343978
- Shen, H., Sun, C. C., Kang, L., Tan, X., Shi, P., Wang, L., Liu, E., & Gong, J. (2021). Low-dose salinomycin inhibits breast cancer metastasis by repolarizing tumor hijacked macrophages toward the M1 phenotype. European Journal of Pharmaceutical Sciences, 157, 105629. https://doi.org/10.1016/j.ejps.2020.105629
- Skakuj, K., Wang, S., Qin, L., Lee, A., Zhang, B., & Mirkin, C. A. (2018). Conjugation chemistry-dependent T-cell activation with spherical nucleic acids. Journal of the American Chemical Society, 140(4), 1227–1230. https://doi.org/10.1021/jacs.7b12579
- Somensi, N., Rabelo, T. K., Guimaraes, A. G., Quintans-Junior, L. J., de Souza Araujo, A. A., Moreira, J. C. F., & Gelain, D. P. (2019). Carvacrol suppresses LPS-induced pro-inflammatory activation in RAW 264.7 macrophages through ERK1/2 and NF-kB pathway. International Immunopharmacology, 75, 105743. https://doi.org/10.1016/j.intimp.2019.105743
- Suntres, Z. E., Coccimiglio, J., & Alipour, M. (2015). The bioactivity and toxicological actions of carvacrol. Critical Reviews in Food Science and Nutrition, 55(3), 304–318. https://doi.org/10.1080/10408398.2011.653458
- Turner, D. L., Gordon, C. L., & Farber, D. L. (2014). Tissue-resident T cells, in situ immunity and transplantation. Immunological Reviews, 258(1), 150–166. https://doi.org/10.1111/imr.12149
- van Ingen, E., Foks, A. C., Woudenberg, T., van der Bent, M. L., de Jong, A., Hohensinner, P. J., Wojta, J., Bot, I., Quax, P. H. A., & Nossent, A. Y. (2021). Inhibition of microRNA-494-3p activates Wnt signaling and reduces proinflammatory macrophage polarization in atherosclerosis. Molecular Therapy - Nucleic Acids, 26, 1228–1239. https://doi.org/10.1016/j.omtn.2021.10.027
- Wang, Z., Zhou, L., Xiong, Y., Yu, S., Li, H., Fan, J., Li, F., Su, Z., Song, J., Sun, Q., Liu, S. S., Xia, Y., Zhao, L., Li, S., Guo, F., Huang, P., Carson, D. A., & Lu, D. (2019). Salinomycin exerts anti-colorectal cancer activity by targeting the beta-catenin/T-cell factor complex. British Journal of Pharmacology, 176(17), 3390–3406. https://doi.org/10.1111/bph.14770
- Xu, Y., Xu, W., Liu, W., Chen, G., Jiang, S., Chen, J., Jian, X., Zhang, H., Liu, P., & Mu, Y. (2021). Yiguanjian decoction inhibits macrophage M1 polarization and attenuates hepatic fibrosis induced by CCl(4)/2-AAF. Pharmaceutical Biology, 59(1), 1150–1160. https://doi.org/10.1080/13880209.2021.1961820
- Yan, C., Kuang, W., Jin, L., Wang, R., Niu, L., Xie, C., Ding, J., Liao, Y., Wang, L., Wan, H., & Ma, G. (2023). Carvacrol protects mice against LPS-induced sepsis and attenuates inflammatory response in macrophages by modulating the ERK1/2 pathway. Scientific Reports, 13(1), 12809. https://doi.org/10.1038/s41598-023-39665-7
- Yang, Z., Xie, H., Wan, J., Wang, Y., Zhang, L., Zhou, K., Tang, H., Zhao, W., Wang, H., Song, P., & Zheng, S. (2023). A nanotherapeutic strategy that engages cytotoxic and immunosuppressive activities for the treatment of cancer recurrence following organ transplantation. eBioMedicine, 92, 104594. https://doi.org/10.1016/j.ebiom.2023.104594
- Yap, M., Brouard, S., Pecqueur, C., & Degauque, N. (2015). Targeting CD8 T-cell metabolism in transplantation. Frontiers in Immunology, 6, 547. https://doi.org/10.3389/fimmu.2015.00547
- Yu, G., Xu, X., Vu, M. D., Kilpatrick, E. D., & Li, X. C. (2006). NK cells promote transplant tolerance by killing donor antigen-presenting cells. The Journal of Experimental Medicine, 203(8), 1851–1858. https://doi.org/10.1084/jem.20060603
- Yu, J., Li, P., Li, Z., Li, Y., Luo, J., Su, W., & Liang, D. (2022). Topical administration of 0.3% tofacitinib suppresses M1 macrophage polarization and allograft corneal rejection by blocking STAT1 activation in the rat cornea. Translational Vision Science & Technology, 11(3), 34. https://doi.org/10.1167/tvst.11.3.34
- Zhao, W., Chen, L., Zhou, H., Deng, C., Han, Q., Chen, Y., Wu, Q., & Li, S. (2021). Protective effect of carvacrol on liver injury in type 2 diabetic db/db mice. Molecular Medicine Reports, 24(5), 741. https://doi.org/10.3892/mmr.2021.12381
- Zhao, W., Deng, C., Han, Q., Xu, H., & Chen, Y. (2020). Carvacrol may alleviate vascular inflammation in diabetic db/db mice. International Journal of Molecular Medicine, 46(3), 977–988. https://doi.org/10.3892/ijmm.2020.4654
- Zhao, X., di, Q., Liu, H., Quan, J., Ling, J., Zhao, Z., Xiao, Y., Wu, H., Wu, Z., Song, W., An, H., & Chen, W. (2022). MEF2C promotes M1 macrophage polarization and Th1 responses. Cellular & Molecular Immunology, 19(4), 540–553. https://doi.org/10.1038/s41423-022-00841-w
- Zhao, X., Zhang, K., Daniel, P., Wisbrun, N., Fuchs, H., & Fan, H. (2019). Delayed allogeneic skin graft rejection in CD26-deficient mice. Cellular & Molecular Immunology, 16(6), 557–567. https://doi.org/10.1038/s41423-018-0009-z
- Zheng, K., Wu, S. Z., Lv, Y. W., Pang, P., Deng, L., Xu, H. C., Shi, Y. C., & Chen, X. Y. (2021). Carvacrol inhibits the excessive immune response induced by influenza virus a via suppressing viral replication and TLR/RLR pattern recognition. Journal of Ethnopharmacology, 268, 113555. https://doi.org/10.1016/j.jep.2020.113555
- Zhou, K., Chen, X., Zhang, L., Yang, Z., Zhu, H., Guo, D., Su, R., Chen, H., Li, H., Song, P., Xu, X., Wang, H., Zheng, S., & Xie, H. (2021). Targeting peripheral immune organs with self-assembling prodrug nanoparticles ameliorates allogeneic heart transplant rejection. American Journal of Transplantation, 21(12), 3871–3882. https://doi.org/10.1111/ajt.16748
Citing Literature
