Altered expression of genes controlling metabolism characterizes the tissue response to immune injury in lupus

Abstract

To compare lupus pathogenesis in disparate tissues, we analyzed gene expression profiles of human discoid lupus erythematosus (DLE) and lupus nephritis (LN). We found common increases in myeloid cell-defining gene sets and decreases in genes controlling glucose and lipid metabolism in lupus-affected skin and kidney. Regression models in DLE indicated increased glycolysis was correlated with keratinocyte, endothelial, and inflammatory cell transcripts, and decreased tricarboxylic (TCA) cycle genes were correlated with the keratinocyte signature. In LN, regression models demonstrated decreased glycolysis and TCA cycle genes were correlated with increased endothelial or decreased kidney cell transcripts, respectively. Less severe glomerular LN exhibited similar alterations in metabolism and tissue cell transcripts before monocyte/myeloid cell infiltration in some patients. Additionally, changes to mitochondrial and peroxisomal transcripts were associated with specific cells rather than global signal changes. Examination of murine LN gene expression demonstrated metabolic changes were not driven by acute exposure to type I interferon and could be restored after immunosuppression. Finally, expression of HAVCR1, a tubule damage marker, was negatively correlated with the TCA cycle signature in LN models. These results indicate that altered metabolic dysfunction is a common, reversible change in lupus-affected tissues and appears to reflect damage downstream of immunologic processes.

The Genetic Landscape of Cutaneous Lupus Erythematosus

“…Apoptotic keratinocytes contribute to the pathogenesis of CLE via the release of cellular debris, which results in a positive feedback loop of inflammation. Recent work by Kingsmore et al ( 71 ) noted increased apoptotic mitochondrial gene signatures in DLE and lupus nephritis, suggesting a role for the intrinsic apoptotic pathway, and positive correlation with inflammatory cell signatures supports the intrinsic link of apoptosis with inflammation. Gene set expression analysis with microarray and RNA-sequencing of CLE skin and blood identified other genes, such as GZMB , BAX , and various caspases ( CASP8 / 10 ) among others ( 1 , 64 , 72 – 75 ).…”

Immune gene expression and functional networks in distinct lupus nephritis classes

“… 21 However, it has been demonstrated in animal models that altered metabolic dysfunction is a reversible change in lupus affected tissues, not driven by type I IFN exposure, and correct modulation can be restored after immunosuppression in animal models. 28 …”

“…The presence of type I IFN signalling has been associated with mitochondrial abnormalities, leading to mitochondrial insufficiency and increased cell death as a regulatory mechanism in persistent type I IFN response 21. However, it has been demonstrated in animal models that altered metabolic dysfunction is a reversible change in lupus affected tissues, not driven by type I IFN exposure, and correct modulation can be restored after immunosuppression in animal models 28…”

Augmented glucose dependency of autoreactive B cells provides a treatment target for lupus

“…The following GO terms were used to generate the Activated B Cell, Pentose Phosphate Pathway, and Glutamine Metabolism gene sets: GO:0002312-B cell activation involved in immune response, GO:0006098-Pentose phosphate shunt, and GO:0006541 glutamine metabolic process. The glycolysis, oxidative phosphorylation, TCA cycle, and fatty acid oxidation gene signatures have been previously described 59 . The B-cell, plasma cell, T-cell, activated T-cell, and myeloid-cell signatures were derived from Mouse CellScan, a tool for the identification of cellular origin of mouse gene-expression datasets.…”