Dataset Information

Graft Site Microenvironment Determines Dendritic Cell Trafficking Through the CCR7-CCL19/21 Axis.

ABSTRACT:

Purpose

The graft site microenvironment has a profound effect on alloimmunity and graft survival. We aimed to study the kinetics and phenotype of trafficking antigen-presenting cells (APC) to the draining lymph nodes (DLNs) in a mouse model of corneal transplantation, and to evaluate the homing mechanisms through which graft site inflammation controls APC trafficking.

Methods

Allogeneic donor corneas were transplanted onto inflamed or quiescent graft beds. Host- (YAe+) and donor (CD45.1+ or eGFP+)-derived APCs were analyzed by flow cytometry. Protein and mRNA expression of the CC chemokine receptor (CCR)7 ligands CCL19 and CCL21 were assessed using ELISA and Real-Time qPCR, respectively. Transwell migration assay was performed to assess the effect of DLNs isolated from hosts with inflamed graft beds on mature bone marrow-derived dendritic cells (BMDCs).

Results

We found that inflamed graft sites greatly promote the trafficking of both recipient- and graft-derived APCs, in particular mature CCR7+ CD11c+ dendritic cells (DC). CCL19 and CCL21 were expressed at significantly higher levels in the DLNs of recipients with inflamed graft beds. The supernatant of DLNs from recipients with inflamed graft beds induced a marked increase in mature DC migration compared with supernatant from recipients with quiescent graft beds in a transwell assay. This effect was abolished by neutralizing CCL19 or CCL21. These data suggest that graft site inflammation increases the expression of CCR7 ligands in the DLNs, which promote mature DC homing and allorejection.

Conclusions

We conclude that the graft site microenvironment plays a critical role in alloimmunity by determining DC trafficking through the CCR7-CCL19/21 axis.

SUBMITTER: Hua J

PROVIDER: S-EPMC4819620 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Publications

Graft Site Microenvironment Determines Dendritic Cell Trafficking Through the CCR7-CCL19/21 Axis.

Hua Jing J Stevenson William W Dohlman Thomas H TH Inomata Takenori T Tahvildari Maryam M Calcagno Narghes N Pirmadjid Negar N Sadrai Zahra Z Chauhan Sunil K SK Dana Reza R

Investigative ophthalmology & visual science 20160301 3

<h4>Purpose</h4>The graft site microenvironment has a profound effect on alloimmunity and graft survival. We aimed to study the kinetics and phenotype of trafficking antigen-presenting cells (APC) to the draining lymph nodes (DLNs) in a mouse model of corneal transplantation, and to evaluate the homing mechanisms through which graft site inflammation controls APC trafficking.<h4>Methods</h4>Allogeneic donor corneas were transplanted onto inflamed or quiescent graft beds. Host- (YAe+) and donor ( ...[more]

PMID: 27031839

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Project description:BackgroundThe study of CCR7/CCL19 chemokine axis and breast cancer (BC) prognosis and metastasis is a current hot topic. We constructed a ceRNA network and risk-prognosis model based on CCR7/CCL19.MethodsBased on the lncRNA, miRNA and mRNA expression data downloaded from the TCGA database, we used the starbase website to find the lncRNA and miRNA of CCR7/CCL19 and established the ceRNA network. The 1008 BC samples containing survival data were divided into Train group (504 cases) and Test group (504 cases) using R "caret" package. Then we constructed a prognostic risk model using RNA screened by univariate Cox analysis in the Train group and validated it in the Test and All groups. In addition, we explored the correlation between riskScores and clinical trials and immune-related factors (22 immune-infiltrating cells, tumor microenvironment, 13 immune-related pathways and 24 HLA genes). After transfection with knockdown CCR7, we observed the activity and migration ability of MDA-MB-231 and MCF-7 cells using CCK8, scratch assays and angiogenesis assays. Finally, qPCR was used to detect the expression levels of five RNAs in the prognostic risk model in MDA-MB-231 and MCF-7 cell.ResultsPatients with high expression of CCR7 and CCL19 had significantly higher overall survival times than those with low expression. The ceRNA network is constructed by 3 pairs of mRNA-miRNA pairs and 8 pairs of miRNA-lncRNA. After multivariate Cox analysis, we obtained a risk prognostic model: riskScore= -1.544 *`TRG-AS1`+ 0.936 * AC010327.5 + 0.553 *CCR7 -0.208 *CCL19 -0.315 *`hsa-let-7b-5p. Age, stage and riskScore can all be used as independent risk factors for BC prognosis. By drug sensitivity analysis, we found 5 drugs targeting CCR7 (convolamine, amikacin, AH-23,848, ondansetron, flucloxacillin). After transfection with knockdown CCR7, we found a significant reduction in cell activity and migration capacity in MDA-MB-231 cells.ConclusionWe constructed the first prognostic model based on the CCR7/CCL19 chemokine axis in BC and explored its role in immune infiltration, tumor microenvironment, and HLA genes.

Dataset Information

Graft Site Microenvironment Determines Dendritic Cell Trafficking Through the CCR7-CCL19/21 Axis.

Purpose

Methods

Results

Conclusions

Publications

Graft Site Microenvironment Determines Dendritic Cell Trafficking Through the CCR7-CCL19/21 Axis.

Similar Datasets

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