ECDI‐fixed donor splenocytes prolong skin allograft survival by promoting M2 macrophage polarization and inducing regulatory T cells
Abstract Rejection is a common complication of allogeneic tissue transplantation. Fixation of splenocytes (SP) with 1‐ethyl‐3‐(3'‐dimethylaminopropyl)‐carbodiimide (ECDI) induces immune tolerance in recipients post‐transplantation; however, the mechanism underlying this effect remains unclear....
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-11-01
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| Series: | FASEB BioAdvances |
| Subjects: | |
| Online Access: | https://doi.org/10.1096/fba.2019-00029 |
| _version_ | 1828399814573817856 |
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| author | Bo Zhou Yuan Zhang Dongliang Zhang Yun Zhang Jiangang Xie Xuexin Zhang Jianke Ding Yingjun Su Shuzhong Guo Ran Zhuang |
| author_facet | Bo Zhou Yuan Zhang Dongliang Zhang Yun Zhang Jiangang Xie Xuexin Zhang Jianke Ding Yingjun Su Shuzhong Guo Ran Zhuang |
| author_sort | Bo Zhou |
| collection | DOAJ |
| description | Abstract Rejection is a common complication of allogeneic tissue transplantation. Fixation of splenocytes (SP) with 1‐ethyl‐3‐(3'‐dimethylaminopropyl)‐carbodiimide (ECDI) induces immune tolerance in recipients post‐transplantation; however, the mechanism underlying this effect remains unclear. Here, we determined the mechanisms of ECDI‐fixed donor SP (ECDI‐SP) in inducing tolerance in skin allograft transplantation. C57BL/6‐recipient mice that received Balb/c full‐thickness skin transplants with two infusions of donor‐derived ECDI‐SP, along with rapamycin showed superior skin allograft survival and lower inflammatory cell infiltration than mice that received rapamycin‐only treatment. In ECDI‐SP‐treated mice, the levels of anti‐inflammatory cytokines such as interleukin (IL)‐10 in sera were markedly increased, whereas the expression of inflammatory cytokines was significantly suppressed. Splenic macrophages were significantly polarized to the alternative activated macrophage (M2) phenotype, with expansion of CD4+Foxp3+ regulatory T cells (Tregs) in the spleen and draining lymph nodes. Allostimulatory activity of ECDI‐SP in vitro and donor‐specific ex vivo hyporesponsiveness were observed. C57BL/6 macrophages engulfed allogeneic Balb/c‐derived ECDI‐SP, polarized to the M2 phenotype, with pronounced cAMP response element‐binding (CREB) protein phosphorylation. By facilitating increased IL‐10 expression, ECDI‐SP induced M2 polarization and Treg production, inhibiting effector T‐cell proliferation. Thus, ECDI‐SP modulates macrophage M2 polarization by increasing CREB phosphorylation and promoting Treg production to suppress allogeneic skin graft rejection. |
| first_indexed | 2024-12-10T09:22:56Z |
| format | Article |
| id | doaj.art-3a4bc1cefdd7464c9ce51a28ea3388df |
| institution | Directory Open Access Journal |
| issn | 2573-9832 |
| language | English |
| last_indexed | 2024-12-10T09:22:56Z |
| publishDate | 2019-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | FASEB BioAdvances |
| spelling | doaj.art-3a4bc1cefdd7464c9ce51a28ea3388df2022-12-22T01:54:37ZengWileyFASEB BioAdvances2573-98322019-11-0111170671810.1096/fba.2019-00029ECDI‐fixed donor splenocytes prolong skin allograft survival by promoting M2 macrophage polarization and inducing regulatory T cellsBo Zhou0Yuan Zhang1Dongliang Zhang2Yun Zhang3Jiangang Xie4Xuexin Zhang5Jianke Ding6Yingjun Su7Shuzhong Guo8Ran Zhuang9Department of Immunology Fourth Military Medical University Xi'an ChinaTransplant Immunology Laboratory Fourth Military Medical University Xi'an ChinaDepartment of Plastic and Reconstructive Surgery Xijing Hospital Fourth Military Medical University Xi'an ChinaDepartment of Immunology Fourth Military Medical University Xi'an ChinaTransplant Immunology Laboratory Fourth Military Medical University Xi'an ChinaTransplant Immunology Laboratory Fourth Military Medical University Xi'an ChinaDepartment of Plastic and Reconstructive Surgery Xijing Hospital Fourth Military Medical University Xi'an ChinaDepartment of Plastic and Reconstructive Surgery Xijing Hospital Fourth Military Medical University Xi'an ChinaDepartment of Plastic and Reconstructive Surgery Xijing Hospital Fourth Military Medical University Xi'an ChinaDepartment of Immunology Fourth Military Medical University Xi'an ChinaAbstract Rejection is a common complication of allogeneic tissue transplantation. Fixation of splenocytes (SP) with 1‐ethyl‐3‐(3'‐dimethylaminopropyl)‐carbodiimide (ECDI) induces immune tolerance in recipients post‐transplantation; however, the mechanism underlying this effect remains unclear. Here, we determined the mechanisms of ECDI‐fixed donor SP (ECDI‐SP) in inducing tolerance in skin allograft transplantation. C57BL/6‐recipient mice that received Balb/c full‐thickness skin transplants with two infusions of donor‐derived ECDI‐SP, along with rapamycin showed superior skin allograft survival and lower inflammatory cell infiltration than mice that received rapamycin‐only treatment. In ECDI‐SP‐treated mice, the levels of anti‐inflammatory cytokines such as interleukin (IL)‐10 in sera were markedly increased, whereas the expression of inflammatory cytokines was significantly suppressed. Splenic macrophages were significantly polarized to the alternative activated macrophage (M2) phenotype, with expansion of CD4+Foxp3+ regulatory T cells (Tregs) in the spleen and draining lymph nodes. Allostimulatory activity of ECDI‐SP in vitro and donor‐specific ex vivo hyporesponsiveness were observed. C57BL/6 macrophages engulfed allogeneic Balb/c‐derived ECDI‐SP, polarized to the M2 phenotype, with pronounced cAMP response element‐binding (CREB) protein phosphorylation. By facilitating increased IL‐10 expression, ECDI‐SP induced M2 polarization and Treg production, inhibiting effector T‐cell proliferation. Thus, ECDI‐SP modulates macrophage M2 polarization by increasing CREB phosphorylation and promoting Treg production to suppress allogeneic skin graft rejection.https://doi.org/10.1096/fba.2019-00029donor‐specific toleranceECDI‐SPtransplantation rejection |
| spellingShingle | Bo Zhou Yuan Zhang Dongliang Zhang Yun Zhang Jiangang Xie Xuexin Zhang Jianke Ding Yingjun Su Shuzhong Guo Ran Zhuang ECDI‐fixed donor splenocytes prolong skin allograft survival by promoting M2 macrophage polarization and inducing regulatory T cells FASEB BioAdvances donor‐specific tolerance ECDI‐SP transplantation rejection |
| title | ECDI‐fixed donor splenocytes prolong skin allograft survival by promoting M2 macrophage polarization and inducing regulatory T cells |
| title_full | ECDI‐fixed donor splenocytes prolong skin allograft survival by promoting M2 macrophage polarization and inducing regulatory T cells |
| title_fullStr | ECDI‐fixed donor splenocytes prolong skin allograft survival by promoting M2 macrophage polarization and inducing regulatory T cells |
| title_full_unstemmed | ECDI‐fixed donor splenocytes prolong skin allograft survival by promoting M2 macrophage polarization and inducing regulatory T cells |
| title_short | ECDI‐fixed donor splenocytes prolong skin allograft survival by promoting M2 macrophage polarization and inducing regulatory T cells |
| title_sort | ecdi fixed donor splenocytes prolong skin allograft survival by promoting m2 macrophage polarization and inducing regulatory t cells |
| topic | donor‐specific tolerance ECDI‐SP transplantation rejection |
| url | https://doi.org/10.1096/fba.2019-00029 |
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