Background Autoimmune and inflammatory diseases such as systemic lupus erythematous (SLE) affect tissues throughout the body. Alterations to inflammatory cell metabolism are often cited as a contributing factor in diseases such as lupus¹, however, changes to metabolism in diseased tissues are poorly understood. Therefore, we investigated changes to cellular metabolic processes in the tissues affected by SLE as well as samples from other inflammatory skin diseases.

Methods Gene expression data collected from patients with lupus nephritis (LN) glomerulus (GL), LN tubulointerstitium (TI), discoid lupus erythematosus (DLE), psoriasis (PSO), atopic dermatitis (AD), and systemic sclerosis (SSc), or murine LN was obtained from Gene Expression Omnibus. Enrichment of metabolic and cellular signature in individual samples was analyzed using Gene Set Variation Analysis (GSVA). Stepwise regression and classification and regression tree (CART) analyses were performed to determine correlations between each metabolic signature and all cellular signatures in each diseased tissue.

Results Comprehensive gene expression analysis of samples derived from glomerular and tubulointerstitial LN kidneys, and DLE, PSO, AD, and SSc skin revealed concurrent changes to genes reflective of cellular metabolic processes and cellular transcripts. In lupus-affected tissues there were shared decreases to metabolic gene signatures², whereas in other inflammatory skin diseases some metabolic transcripts were increased. In glomerular LN, decreased glycolysis gene expression was correlated with increased endothelial cell transcripts². Conversely, regression analyses demonstrated that decreased tricarboxylic acid (TCA) cycle and lipid metabolism signatures reflected decreased kidney cell transcripts, which was confirmed by the negative relationship between the TCA cycle signature and expression of the tubule damage marker, HAVCR1.¹ Indeed, similar alterations to metabolism were observed in some less severe LN patients, in which inflammatory cell transcripts were not yet increased.² Although interferon can induce metabolic changes at the transcriptional level,³ examination of metabolic gene expression in the murine interferon alpha-accelerated LN model revealed that metabolic changes were not driven by acute exposure to type I interferon.² Moreover, evaluation of metabolic changes in murine LN following various treatments demonstrated that metabolic gene expression could be restored with immunosuppressive therapy.² Regression analyses in DLE and PSO demonstrated that there was a positive correlation between the glycolysis signature and the keratinocyte signature, whereas in PSO, AD, and SSc the glycolysis signature was positively correlated with the monocyte/myeloid cell signature.

Conclusion These results indicate that altered metabolic dysfunction is a common change in lupus- and inflammatory disease-affected tissues and appears to reflect immunologic damage.

References

1. Morel L. Immunometabolism in systemic lupus erythematosus. Nat Rev Rheumatol. 2017;13(5):280–290.

2. Kingsmore KM, Bachali P, Catalina MD, et al. Altered expression of genes controlling metabolism characterizes the tissue response to immune injury in lupus. Sci Rep. 2021;11(1):14789.

3. Wu D, Sanin DE, Everts B, et al. Type 1 interferons induce changes in core metabolism that are critical for immune function. Immunity 2016;44(6):1325–1336.