Donor intravascular monocyte trafficking: a potential therapeutic target for primary graft dysfunction following lung transplantation?

Lamb, Christopher A; Kirby, John A.

doi:10.1136/thoraxjnl-2017-210274

Cited by 1 publication

(1 citation statement)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While neutrophil depletion can ameliorate PGD, it is not clinically feasible given their importance in pathogen clearance. We and others have recently demonstrated that donor human (CD14 low CD16 high ) and murine (CX3CR1 + Ly6C low CCR2 -) non-classical monocytes (NCM) retained in the vascular space of the donor lungs recruit neutrophils to transplanted lungs through the release of CXCL2 (5)(6)(7)(8). Genetic and pharmacological depletion of NCM attenuates neutrophil recruitment and prevents PGD.…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between nonclassical monocytes and alveolar macrophages mediates transplant ischemia-reperfusion injury through classical monocyte recruitment

Kurihara¹,

Lecuona²,

Wu³

et al. 2021

JCI Insight

View full text Add to dashboard Cite

Primary Graft Dysfunction (PGD) is the predominant cause of early graft loss following lung transplantation. We recently demonstrated that donor pulmonary intravascular non-classical 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 flowcytometry revealed that depletion of donor NCM abrogated CM recruitment, single-cell RNA-seq identified donor alveolar macrophages (AM) as predominant CCL2 secretors. Unbiased transcriptomic analysis of murine tissues combined with murine knockouts and chimeras indicated that IL1β production by donor NCM was responsible for the early activation of AM and CCL2 release. IL1β 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 IL1R-dependent activation of the PKC and NFκB-pathway. Accordingly, we show that IL1β-dependent paracrine interaction between donor NCM and AM leads to recruitment of recipient CM necessary for PGD. Since depletion of donor NCM, IL1β or IL1R antagonism, and inflammasome inhibition, abrogated recruitment of CM as well as PGD, and are feasible using FDA-approved compounds, our findings may have potential for clinical translation.

show abstract

Section: Introductionmentioning

confidence: 99%