Iguratimod Attenuates Macrophage Polarization and Antibody-Mediated Rejection After Renal Transplant by Regulating KLF4
Background: This study aimed to explore the effect and mechanism of iguratimod (IGT) on M1 macrophage polarization and antibody-mediated rejection (ABMR) after renal transplant.Methods: Bioinformatics analysis was performed using three public databases derived from the GEO database. Sprague–Dawley (...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-05-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.865363/full |
| _version_ | 1818200498220564480 |
|---|---|
| author | Zhou Hang Jintao Wei Ming Zheng Zeping Gui Hao Chen Li Sun Shuang Fei Zhijian Han Jun Tao Zijie Wang Ruoyun Tan Min Gu Min Gu |
| author_facet | Zhou Hang Jintao Wei Ming Zheng Zeping Gui Hao Chen Li Sun Shuang Fei Zhijian Han Jun Tao Zijie Wang Ruoyun Tan Min Gu Min Gu |
| author_sort | Zhou Hang |
| collection | DOAJ |
| description | Background: This study aimed to explore the effect and mechanism of iguratimod (IGT) on M1 macrophage polarization and antibody-mediated rejection (ABMR) after renal transplant.Methods: Bioinformatics analysis was performed using three public databases derived from the GEO database. Sprague–Dawley (SD) rats were pre-sensitized with donors of Wistar rats in skin transplantation and a rat renal transplant ABMR model was established from the donors to skin pre-sensitized recipients. Subsequently, IGT was treated on the ABMR model. Routine staining and immunofluorescence (IF) staining were performed to observe the pathological changes in each group and flow cytometry was performed to detect the changes of DSA titers in peripheral blood. In addition, bone-marrow-derived macrophage (BMDM) was extracted and interfered with IGT to explore the effect of IGT in vivo. PCR, IF staining, and Western blot were used to detect the expression of related genes and proteins.Results: Bioinformatics analysis revealed that several immune cells were significantly infiltrated in the ABMR allograft, while M1 macrophage was noticed with the most significance. Results of IF staining and PCR proved the findings of the bioinformatics analysis. Based on this, IGT was observed to significantly attenuate the degree of peritubular capillary vasculitis and arteriolitis in the rat renal transplant ABMR model, whereas it decreases the expression of C4d and reduces the titer of DSA. Results in vitro suggested that M1 macrophage-related transcripts and proteins were significantly reduced by the treatment of IGT in a dose- and time-dependent manner. Furthermore, IGT intervention could remarkably decrease the expression of KLF4.Conclusion: Polarization of M1 macrophages may aggravate ABMR after renal transplant by promoting DSA-mediated endothelial cell injury, and IGT may attenuate the pathogenesis of ABMR by targeting KLF4. |
| first_indexed | 2024-12-12T02:38:37Z |
| format | Article |
| id | doaj.art-3a95c32360d941e3bde74a2e950d518e |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-12T02:38:37Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-3a95c32360d941e3bde74a2e950d518e2022-12-22T00:41:13ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-05-011310.3389/fphar.2022.865363865363Iguratimod Attenuates Macrophage Polarization and Antibody-Mediated Rejection After Renal Transplant by Regulating KLF4Zhou Hang0Jintao Wei1Ming Zheng2Zeping Gui3Hao Chen4Li Sun5Shuang Fei6Zhijian Han7Jun Tao8Zijie Wang9Ruoyun Tan10Min Gu11Min Gu12Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Emergency Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaBackground: This study aimed to explore the effect and mechanism of iguratimod (IGT) on M1 macrophage polarization and antibody-mediated rejection (ABMR) after renal transplant.Methods: Bioinformatics analysis was performed using three public databases derived from the GEO database. Sprague–Dawley (SD) rats were pre-sensitized with donors of Wistar rats in skin transplantation and a rat renal transplant ABMR model was established from the donors to skin pre-sensitized recipients. Subsequently, IGT was treated on the ABMR model. Routine staining and immunofluorescence (IF) staining were performed to observe the pathological changes in each group and flow cytometry was performed to detect the changes of DSA titers in peripheral blood. In addition, bone-marrow-derived macrophage (BMDM) was extracted and interfered with IGT to explore the effect of IGT in vivo. PCR, IF staining, and Western blot were used to detect the expression of related genes and proteins.Results: Bioinformatics analysis revealed that several immune cells were significantly infiltrated in the ABMR allograft, while M1 macrophage was noticed with the most significance. Results of IF staining and PCR proved the findings of the bioinformatics analysis. Based on this, IGT was observed to significantly attenuate the degree of peritubular capillary vasculitis and arteriolitis in the rat renal transplant ABMR model, whereas it decreases the expression of C4d and reduces the titer of DSA. Results in vitro suggested that M1 macrophage-related transcripts and proteins were significantly reduced by the treatment of IGT in a dose- and time-dependent manner. Furthermore, IGT intervention could remarkably decrease the expression of KLF4.Conclusion: Polarization of M1 macrophages may aggravate ABMR after renal transplant by promoting DSA-mediated endothelial cell injury, and IGT may attenuate the pathogenesis of ABMR by targeting KLF4.https://www.frontiersin.org/articles/10.3389/fphar.2022.865363/fullmacrophage polarizationantibody-mediated rejectionKLF4iguratimodkidney transplant |
| spellingShingle | Zhou Hang Jintao Wei Ming Zheng Zeping Gui Hao Chen Li Sun Shuang Fei Zhijian Han Jun Tao Zijie Wang Ruoyun Tan Min Gu Min Gu Iguratimod Attenuates Macrophage Polarization and Antibody-Mediated Rejection After Renal Transplant by Regulating KLF4 Frontiers in Pharmacology macrophage polarization antibody-mediated rejection KLF4 iguratimod kidney transplant |
| title | Iguratimod Attenuates Macrophage Polarization and Antibody-Mediated Rejection After Renal Transplant by Regulating KLF4 |
| title_full | Iguratimod Attenuates Macrophage Polarization and Antibody-Mediated Rejection After Renal Transplant by Regulating KLF4 |
| title_fullStr | Iguratimod Attenuates Macrophage Polarization and Antibody-Mediated Rejection After Renal Transplant by Regulating KLF4 |
| title_full_unstemmed | Iguratimod Attenuates Macrophage Polarization and Antibody-Mediated Rejection After Renal Transplant by Regulating KLF4 |
| title_short | Iguratimod Attenuates Macrophage Polarization and Antibody-Mediated Rejection After Renal Transplant by Regulating KLF4 |
| title_sort | iguratimod attenuates macrophage polarization and antibody mediated rejection after renal transplant by regulating klf4 |
| topic | macrophage polarization antibody-mediated rejection KLF4 iguratimod kidney transplant |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.865363/full |
| work_keys_str_mv | AT zhouhang iguratimodattenuatesmacrophagepolarizationandantibodymediatedrejectionafterrenaltransplantbyregulatingklf4 AT jintaowei iguratimodattenuatesmacrophagepolarizationandantibodymediatedrejectionafterrenaltransplantbyregulatingklf4 AT mingzheng iguratimodattenuatesmacrophagepolarizationandantibodymediatedrejectionafterrenaltransplantbyregulatingklf4 AT zepinggui iguratimodattenuatesmacrophagepolarizationandantibodymediatedrejectionafterrenaltransplantbyregulatingklf4 AT haochen iguratimodattenuatesmacrophagepolarizationandantibodymediatedrejectionafterrenaltransplantbyregulatingklf4 AT lisun iguratimodattenuatesmacrophagepolarizationandantibodymediatedrejectionafterrenaltransplantbyregulatingklf4 AT shuangfei iguratimodattenuatesmacrophagepolarizationandantibodymediatedrejectionafterrenaltransplantbyregulatingklf4 AT zhijianhan iguratimodattenuatesmacrophagepolarizationandantibodymediatedrejectionafterrenaltransplantbyregulatingklf4 AT juntao iguratimodattenuatesmacrophagepolarizationandantibodymediatedrejectionafterrenaltransplantbyregulatingklf4 AT zijiewang iguratimodattenuatesmacrophagepolarizationandantibodymediatedrejectionafterrenaltransplantbyregulatingklf4 AT ruoyuntan iguratimodattenuatesmacrophagepolarizationandantibodymediatedrejectionafterrenaltransplantbyregulatingklf4 AT mingu iguratimodattenuatesmacrophagepolarizationandantibodymediatedrejectionafterrenaltransplantbyregulatingklf4 AT mingu iguratimodattenuatesmacrophagepolarizationandantibodymediatedrejectionafterrenaltransplantbyregulatingklf4 |