Crosstalk between nonclassical monocytes and alveolar macrophages mediates transplant ischemia-reperfusion injury through classical monocyte recruitment
| Autor: | G. R. Scott Budinger, Félix L. Núñez-Santana, Emilia Lecuona, Hiam Abdala-Valencia, Xianpeng Liu, Wenbin Yang, Haiying Sun, Ziyou Ren, Ali Shilatifard, Mahzad Akbarpour, Qiang Wu, Megan E Kelly, Melissa Querrey, Daniel Kreisel, Sowmya Ravi, Wenjun Li, Emily Cerier, Thalachallour Mohanakumar, Megan L Anderson, Chitaru Kurihara, Ankit Bharat |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male medicine.medical_treatment Primary Graft Dysfunction CCL2 Monocytes Flow cytometry 03 medical and health sciences Mice 0302 clinical medicine Macrophages Alveolar medicine Lung transplantation Animals Humans Neutrophil extravasation Mice Inbred BALB C Transplantation medicine.diagnostic_test Chemistry Organ transplantation Monocyte Inflammasome General Medicine Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Reperfusion Injury Cancer research Medicine medicine.drug Lung Transplantation Research Article |
| Zdroj: | JCI Insight, Vol 6, Iss 6 (2021) JCI Insight |
| ISSN: | 2379-3708 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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