TY - JOUR
T1 - Crosstalk between nonclassical monocytes and alveolar macrophages mediates transplant ischemia-reperfusion injury through classical monocyte recruitment
AU - Kurihara, Chitaru
AU - Lecuona, Emilia
AU - Wu, Qiang
AU - Yang, Wenbin
AU - Núñez-Santana, Félix L.
AU - Akbarpour, Mahzad
AU - Liu, Xianpeng
AU - Ren, Ziyou
AU - Li, Wenjun
AU - Querrey, Melissa
AU - Ravi, Sowmya
AU - Anderson, Megan L.
AU - Cerier, Emily
AU - Sun, Haiying
AU - Kelly, Megan E.
AU - Abdala-Valencia, Hiam
AU - Shilatifard, Ali
AU - Mohanakumar, Thalachallour
AU - Budinger, G. R.Scott
AU - Kreisel, Daniel
AU - Bharat, Ankit
N1 - Publisher Copyright:
Copyright: © 2021, Kurihara et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2021/3/22
Y1 - 2021/3/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85103234131&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.147282
DO - 10.1172/jci.insight.147282
M3 - Article
C2 - 33621212
AN - SCOPUS:85103234131
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 6
M1 - e147282
ER -