Landscape of innate immune system transcriptome and acute T cell–mediated rejection of human kidney allografts
Franco B. Mueller, … , Manikkam Suthanthiran, Thangamani Muthukumar
Franco B. Mueller, … , Manikkam Suthanthiran, Thangamani Muthukumar
Published July 11, 2019
Citation Information: JCI Insight. 2019;4(13):e128014. https://doi.org/10.1172/jci.insight.128014.
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Research Article Immunology Transplantation

Landscape of innate immune system transcriptome and acute T cell–mediated rejection of human kidney allografts

Abstract

Acute rejection of human allografts has been viewed mostly through the lens of adaptive immunity, and the intragraft landscape of innate immunity genes has not been characterized in an unbiased fashion. We performed RNA sequencing of 34 kidney allograft biopsy specimens from 34 adult recipients; 16 were categorized as Banff acute T cell–mediated rejection (TCMR) and 18 as normal. Computational analysis of intragraft mRNA transcriptome identified significantly higher abundance of mRNA for pattern recognition receptors in TCMR compared with normal biopsies, as well as increased expression of mRNAs for cytokines, chemokines, interferons, and caspases. Intragraft levels of calcineurin mRNA were higher in TCMR biopsies, suggesting underimmunosuppression compared with normal biopsies. Cell-type-enrichment analysis revealed higher abundance of dendritic cells and macrophages in TCMR biopsies. Damage-associated molecular patterns, the endogenous ligands for pattern recognition receptors, as well markers of DNA damage were higher in TCMR. mRNA expression patterns supported increased calcium flux and indices of endoplasmic, cellular oxidative, and mitochondrial stress were higher in TCMR. Expression of mRNAs in major metabolic pathways was decreased in TCMR. Our global and unbiased transcriptome profiling identified heightened expression of innate immune system genes during an episode of TCMR in human kidney allografts.

Authors

Franco B. Mueller, Hua Yang, Michelle Lubetzky, Akanksha Verma, John R. Lee, Darshana M. Dadhania, Jenny Z. Xiang, Steven P. Salvatore, Surya V. Seshan, Vijay K. Sharma, Olivier Elemento, Manikkam Suthanthiran, Thangamani Muthukumar

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Figure 2

Intragraft abundance of mRNAs encoding caspases in human kidney allograft biopsies.

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Intragraft abundance of mRNAs encoding caspases in human kidney allograf...
mRNA abundance of inflammatory (A) and apoptosis caspases (B) in TCMR and Normal. The number in each box plot is the median value of mRNA abundance as fragments per kilobase of exon per million reads mapped (FPKM), which normalizes the RNA sequencing data for sequencing depth (per million scaling factor) and the gene length (per kilobase scaling factor) and was assessed with Cufflinks. The fold change (FC) values shown beneath the x axis and the P-FDR were calculated using edgeR. Signaling through PRRs activates caspases. There were strong associations between several PRRs and caspases. As an example, the association between mRNA expression levels of the key inflammatory caspase, caspase 1, and TLR2 (C) or NLRP3 (D) are shown. The strength of the association is expressed as the coefficient of determination (r2). NLRP3 is a key component of the inflammasome, which is a multiprotein complex of receptors and sensors that regulate the activation of caspase 1 and induce inflammation.