Crosstalk between nonclassical monocytes and alveolar macrophages mediates transplant ischemia-reperfusion injury through classical monocyte recruitment
Primary graft dysfunction (PGD) is the predominant cause of early graft loss following lung transplantation. We recently demonstrated that donor pulmonary intravascular nonclassical monocytes (NCM) initiate neutrophil recruitment. Simultaneously, host-origin classical monocytes (CM) permeabilize the...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-03-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.147282 |
| _version_ | 1819122291417546752 |
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| author | Chitaru Kurihara Emilia Lecuona Qiang Wu Wenbin Yang Félix L. Núñez-Santana Mahzad Akbarpour Xianpeng Liu Ziyou Ren Wenjun Li Melissa Querrey Sowmya Ravi Megan L. Anderson Emily Cerier Haiying Sun Megan E. Kelly Hiam Abdala-Valencia Ali Shilatifard Thalachallour Mohanakumar G.R. Scott Budinger Daniel Kreisel Ankit Bharat |
| author_facet | Chitaru Kurihara Emilia Lecuona Qiang Wu Wenbin Yang Félix L. Núñez-Santana Mahzad Akbarpour Xianpeng Liu Ziyou Ren Wenjun Li Melissa Querrey Sowmya Ravi Megan L. Anderson Emily Cerier Haiying Sun Megan E. Kelly Hiam Abdala-Valencia Ali Shilatifard Thalachallour Mohanakumar G.R. Scott Budinger Daniel Kreisel Ankit Bharat |
| author_sort | Chitaru Kurihara |
| collection | DOAJ |
| description | Primary graft dysfunction (PGD) is the predominant cause of early graft loss following lung transplantation. We recently demonstrated that donor pulmonary intravascular nonclassical monocytes (NCM) initiate neutrophil recruitment. Simultaneously, host-origin classical monocytes (CM) permeabilize the vascular endothelium to allow neutrophil extravasation necessary for PGD. Here, we show that a CCL2-CCR2 axis is necessary for CM recruitment. Surprisingly, although intravital imaging and multichannel flow cytometry revealed that depletion of donor NCM abrogated CM recruitment, single cell RNA sequencing identified donor alveolar macrophages (AM) as predominant CCL2 secretors. Unbiased transcriptomic analysis of murine tissues combined with murine KOs and chimeras indicated that IL-1β production by donor NCM was responsible for the early activation of AM and CCL2 release. IL-1β production by NCM was NLRP3 inflammasome dependent and inhibited by treatment with a clinically approved sulphonylurea. Production of CCL2 in the donor AM occurred through IL-1R–dependent activation of the PKC and NF-κB pathway. Accordingly, we show that IL-1β–dependent paracrine interaction between donor NCM and AM leads to recruitment of recipient CM necessary for PGD. Since depletion of donor NCM, IL-1β, or IL-1R antagonism and inflammasome inhibition abrogated recruitment of CM and PGD and are feasible using FDA-approved compounds, our findings may have potential for clinical translation. |
| first_indexed | 2024-12-22T06:50:07Z |
| format | Article |
| id | doaj.art-cb3ce52f508540b4bd16d407b8b2ff90 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-22T06:50:07Z |
| publishDate | 2021-03-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-cb3ce52f508540b4bd16d407b8b2ff902022-12-21T18:35:11ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-03-0166Crosstalk between nonclassical monocytes and alveolar macrophages mediates transplant ischemia-reperfusion injury through classical monocyte recruitmentChitaru KuriharaEmilia LecuonaQiang WuWenbin YangFélix L. Núñez-SantanaMahzad AkbarpourXianpeng LiuZiyou RenWenjun LiMelissa QuerreySowmya RaviMegan L. AndersonEmily CerierHaiying SunMegan E. KellyHiam Abdala-ValenciaAli ShilatifardThalachallour MohanakumarG.R. Scott BudingerDaniel KreiselAnkit BharatPrimary graft dysfunction (PGD) is the predominant cause of early graft loss following lung transplantation. We recently demonstrated that donor pulmonary intravascular nonclassical monocytes (NCM) initiate neutrophil recruitment. Simultaneously, host-origin classical monocytes (CM) permeabilize the vascular endothelium to allow neutrophil extravasation necessary for PGD. Here, we show that a CCL2-CCR2 axis is necessary for CM recruitment. Surprisingly, although intravital imaging and multichannel flow cytometry revealed that depletion of donor NCM abrogated CM recruitment, single cell RNA sequencing identified donor alveolar macrophages (AM) as predominant CCL2 secretors. Unbiased transcriptomic analysis of murine tissues combined with murine KOs and chimeras indicated that IL-1β production by donor NCM was responsible for the early activation of AM and CCL2 release. IL-1β production by NCM was NLRP3 inflammasome dependent and inhibited by treatment with a clinically approved sulphonylurea. Production of CCL2 in the donor AM occurred through IL-1R–dependent activation of the PKC and NF-κB pathway. Accordingly, we show that IL-1β–dependent paracrine interaction between donor NCM and AM leads to recruitment of recipient CM necessary for PGD. Since depletion of donor NCM, IL-1β, or IL-1R antagonism and inflammasome inhibition abrogated recruitment of CM and PGD and are feasible using FDA-approved compounds, our findings may have potential for clinical translation.https://doi.org/10.1172/jci.insight.147282Transplantation |
| spellingShingle | Chitaru Kurihara Emilia Lecuona Qiang Wu Wenbin Yang Félix L. Núñez-Santana Mahzad Akbarpour Xianpeng Liu Ziyou Ren Wenjun Li Melissa Querrey Sowmya Ravi Megan L. Anderson Emily Cerier Haiying Sun Megan E. Kelly Hiam Abdala-Valencia Ali Shilatifard Thalachallour Mohanakumar G.R. Scott Budinger Daniel Kreisel Ankit Bharat Crosstalk between nonclassical monocytes and alveolar macrophages mediates transplant ischemia-reperfusion injury through classical monocyte recruitment JCI Insight Transplantation |
| title | Crosstalk between nonclassical monocytes and alveolar macrophages mediates transplant ischemia-reperfusion injury through classical monocyte recruitment |
| title_full | Crosstalk between nonclassical monocytes and alveolar macrophages mediates transplant ischemia-reperfusion injury through classical monocyte recruitment |
| title_fullStr | Crosstalk between nonclassical monocytes and alveolar macrophages mediates transplant ischemia-reperfusion injury through classical monocyte recruitment |
| title_full_unstemmed | Crosstalk between nonclassical monocytes and alveolar macrophages mediates transplant ischemia-reperfusion injury through classical monocyte recruitment |
| title_short | Crosstalk between nonclassical monocytes and alveolar macrophages mediates transplant ischemia-reperfusion injury through classical monocyte recruitment |
| title_sort | crosstalk between nonclassical monocytes and alveolar macrophages mediates transplant ischemia reperfusion injury through classical monocyte recruitment |
| topic | Transplantation |
| url | https://doi.org/10.1172/jci.insight.147282 |
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