Non-Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock


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 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-1beta production by donor NCM was responsible for the early activation of AM and CCL2 release. IL-1beta 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-kappaB pathway. Accordingly, we show that IL-1beta-dependent paracrine interaction between donor NCM and AM leads to recruitment of recipient CM necessary for PGD. Since depletion of donor NCM, IL-1beta, 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.

Authors: Kurihara C, Lecuona E, Wu Q, Yang W, Núñez-Santana FL, Akbarpour M, Liu X, Ren Z, Li W, Querrey M, Ravi S, Anderson ML, Cerier E, Sun H, Kelly ME, Abdala-Valencia H, Shilatifard A, Mohanakumar T, Budinger GRS, Kreisel D, Bharat A,
Journal: JCI Insight; 2021 Mar 22;6(6):e14728 . doi:10.1172/jci.insight.147282
Year: 2021
PubMed: PMID: 33621212 (Go to PubMed)