Single cell transcriptomics of mouse kidney transplants reveals a myeloid cell pathway for transplant rejection.

Abstract

Myeloid cells are increasingly recognized as major players in transplant rejection. Here, we used a murine kidney transplantation model and single cell transcriptomics to dissect the contribution of myeloid cell subsets and their potential signaling pathways to kidney transplant rejection. Using a variety of bioinformatic techniques, including machine learning, we demonstrate that kidney allograft-infiltrating myeloid cells followed a trajectory of differentiation from monocytes to proinflammatory macrophages, and they exhibited distinct interactions with kidney allograft parenchymal cells. While this process correlated with a unique pattern of myeloid cell transcripts, a top gene identified was Axl, a member of the receptor tyrosine kinase family Tyro3/Axl/Mertk (TAM). Using kidney transplant recipients with Axl gene deficiency, we further demonstrate that Axl augmented intragraft differentiation of proinflammatory macrophages, likely via its effect on the transcription factor Cebpb. This, in turn, promoted intragraft recruitment, differentiation, and proliferation of donor-specific T cells, and it enhanced early allograft inflammation evidenced by histology. We conclude that myeloid cell Axl expression identified by single cell transcriptomics of kidney allografts in our study plays a major role in promoting intragraft myeloid cell and T cell differentiation, and it presents a potentially novel therapeutic target for controlling kidney allograft rejection and improving kidney allograft survival.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1172/jci.insight.141321

Publication Info

Dangi, Anil, Naveen R Natesh, Irma Husain, Zhicheng Ji, Laura Barisoni, Jean Kwun, Xiling Shen, Edward B Thorp, et al. (2020). Single cell transcriptomics of mouse kidney transplants reveals a myeloid cell pathway for transplant rejection. JCI insight, 5(20). p. 141321. 10.1172/jci.insight.141321 Retrieved from https://hdl.handle.net/10161/26155.

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Scholars@Duke

Husain

Irma Husain

Assistant Professor of Medicine
Ji

Zhicheng Ji

Assistant Professor of Biostatistics & Bioinformatics
Barisoni

Laura Barisoni

Professor of Pathology
Kwun

Jean Kwun

Associate Professor in Surgery

Research interests include humoral tolerance to organ transplants in animal model and humans, developing a clinically relevant animal model to study the mechanisms of antibody-mediated rejection (AMR), and establishing a conceptual basis that will translate into therapeutic intervention of AMR.

Shen

Xiling Shen

Adjunct Professor in the Department of Pathology

Dr. Shen’s research interests lie at precision medicine and systems biology. His lab integrates engineering, computational and biological techniques to study cancer, stem cells, microbiota and the nervous system in the gut. This multidisciplinary work has been instrumental in initiating several translational clinical trials in precision therapy. He is the director of the Woo Center for Big Data and Precision Health (DAP) and a core member of the Center for Genomics and Computational Biology (GCB).

Luo

Xunrong Luo

Boyce Haller Distinguished Professor in Nephrology

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