Single-cell transcriptomics of mouse kidney transplants reveals a myeloid cell pathway for transplant rejection.
Myeloid cells are increasingly recognized as a major player 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 demonstrated that kidney allograft-infiltrating myeloid cells followed a trajectory of differentiating from monocytes to pro-inflammatory macrophages, and 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 TAM (Tyro3/Axl/Mertk). Using kidney transplant recipients with Axl gene deficiency, we further demonstrated that Axl augmented intragraft differentiation of pro-inflammatory 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 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 presents a novel therapeutic target for controlling kidney allograft rejection and improving kidney allograft survival.
Dangi, A; Natesh, NR; Husain, I; Ji, Z; Barisoni, L; Kwun, J; Shen, X; Thorp, EB; Luo, X
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