Abstract
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.
Highlights
Primary graft dysfunction (PGD), the clinical manifestation of lung transplant ischemia-reperfusion injury, affects over 50% of lung recipients within the first 72 hours and is the predominant cause of shortterm mortality, as well as chronic lung allograft rejection [1, 2]
We found that anti-CCR2 treatment of the recipients significantly attenuated the number of classical monocytes (CM) recruited to the transplanted lung (Figure 1A)
Since anti-CCR2 antibody treatment could potentially lead to the depletion of the recipient CM, we used Ccr2–/– recipient mice and, found a decrease in the number of CM in the lung allograft (Figure 1B)
Summary
Primary graft dysfunction (PGD), the clinical manifestation of lung transplant ischemia-reperfusion injury, affects over 50% of lung recipients within the first 72 hours and is the predominant cause of shortterm mortality, as well as chronic lung allograft rejection [1, 2]. Host-origin Ly6ChiCCR2+ classical monocytes (CM) are recruited from the spleen to the transplanted lungs, and complementary to the NCM, they mediate extravasation of the recruited neutrophils into the interstitial space by permeabilizing the endothelium through the secretion of IL-1β [9]. Both donor NCM and recipient CM are necessary for neutrophil trafficking into reperfused lung grafts [2]
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