Residual endotoxin induces primary graft dysfunction through ischemia-reperfusion-primed alveolar macrophages

Akbarpour, Mahzad; Lecuona, Emilia; Chiu, Stephen; Wu, Qiang; Querrey, Melissa; Fernández, Ramiro; Nunez-Santana, Felix; Sun, Haiying; Ravi, Sowmya; Kurihara, Chitaru; Walter, James M.; Joshi, Nikita; Ren, Ziyou; Hauser, Alan R.; Kreisel, Daniel; Li, Wenjun; Chandel, Navdeep S.; Misharin, Alexander V.; Mohanakumar, Thalachallour; Budinger, G. R. Scott; Bharat, Ankit

doi:10.1172/jci135838

Cited by 16 publications

(19 citation statements)

References 57 publications

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“…We confirmed the increase in Ccl2 transcription in donor AM by secondary analysis of our previously published RNA-seq data set ( 19 ) ( Figure 3D ), as well as qPCR of donor human and murine AM isolated immediately following reperfusion ( Figure 3E ). To causally link CCL2 secretion by AM-to-CM recruitment, we depleted donor AM using Clo-lip ( 16 ) prior to transplantation and found a significant decrease in the recruitment of CM, as well as neutrophil extravasation, following transplantation ( Figure 3, F and G ). Since pharmacological depletion of donor AM can induce inflammation through cell death, we developed a conditional KO of Ccl2 in the donor AM by crossing Cd169 Cre and Ccl2-rfp fl/fl mice ( 20 ).…”

Section: Resultsmentioning

confidence: 99%

“…Postreperfusion samples were obtained after 15 minutes of reperfusion. Donor NCM were identified from fresh specimens using multicolor flow cytometry, using our previously described protocols ( 16 ), and were isolated 15 minutes following reperfusion. Bronchoscopic bronchoalveolar lavage fluid (BALF) was used to collect donor AM.…”

Section: Methodsmentioning

confidence: 99%

“…Intravenous and intratracheal procedure was performed utilizing an adaptation of previously described methods (16,19). Briefly, 6μg of APC-conjugated anti-CD45 in 100ul of sterile PBS was injected intravenously and allowed to circulate for 3 minutes prior to euthanasia with an overdose of Euthasol.…”

Section: Compartmental Lung Intravenous Staining For Neutrophils Extrmentioning

confidence: 99%

“…Alveolar macrophages (AM) are long lived cells found in the alveoli and airways which have a range of functions in the lungs, including maintenance of homoeostasis and 4 immune surveillance (15). AM induced early reperfusion injury and neutrophil recruitment has been postulated and verified by several groups (5,16).…”

Section: Introductionmentioning

confidence: 99%

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

Kurihara¹,

Lecuona²,

Wu³

et al. 2021

JCI Insight

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Compartmental Lung Intravenous Staining For Neutrophils Extrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Kurihara¹,

Lecuona²,

Wu³

et al. 2021

JCI Insight

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“…The source of the endotoxin is not clear, but it has been suggested that LPS may leak from the gut under ischemia/reperfusion conditions (92). This has major implications in lung transplantation as oxidative stress induced during IRI, coupled with an increase in the endotoxin levels in the donor organ is associated with increased neutrophil recruitment as well as physiological markers of allograft injury mediated by tissue resident alveolar macrophages through TLR4/ MyD88 dependent pathways (93). Consequentially, presence of endotoxin in the lung predisposes the donor organ to the fatal syndrome of primary graft dysfunction (PGD) and compromises the survival of the allograft following lung transplantation.…”

Section: Introductionmentioning

confidence: 99%

Macrophages in Organ Transplantation

et al. 2020

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Current immunosuppressive therapy has led to excellent short-term survival rates in organ transplantation. However, long-term graft survival rates are suboptimal, and a vast number of allografts are gradually lost in the clinic. An increasing number of animal and clinical studies have demonstrated that monocytes and macrophages play a pivotal role in graft rejection, as these mononuclear phagocytic cells recognize alloantigens and trigger an inflammatory cascade that activate the adaptive immune response. Moreover, recent studies suggest that monocytes acquire a feature of memory recall response that is associated with a potent immune response. This form of memory is called “trained immunity,” and it is retained by mechanisms of epigenetic and metabolic changes in innate immune cells after exposure to particular ligands, which have a direct impact in allograft rejection. In this review article, we highlight the role of monocytes and macrophages in organ transplantation and summarize therapeutic approaches to promote tolerance through manipulation of monocytes and macrophages. These strategies may open new therapeutic opportunities to increase long-term transplant survival rates in the clinic.

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TJ-M2010-5 Attenuates Severe Myocardial Ischemia/Reperfusion Injury in Heart Transplantation by Inhibiting MyD88 Homodimerization In Vivo

Heng

Zhou

et al. 2022

J. of Cardiovasc. Trans. Res.

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Residual endotoxin induces primary graft dysfunction through ischemia-reperfusion-primed alveolar macrophages

Cited by 16 publications

References 57 publications

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

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

Macrophages in Organ Transplantation

TJ-M2010-5 Attenuates Severe Myocardial Ischemia/Reperfusion Injury in Heart Transplantation by Inhibiting MyD88 Homodimerization In Vivo

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