Extended Data Fig. 10: Pharmacological inactivation of mitochondrial copper(II) attenuates inflammation in vivo.
From: A druggable copper-signalling pathway that drives inflammation
a, Western blots of copper-signalling effectors in SPMs from mice treated with LPS. Macrophages of several mice were pooled (4–7 mice per condition). b, Western blots of copper-signalling effectors in SPMs from mice subjected to CLP. Macrophages of several mice were pooled (7–8 mice per condition). H3 is a sample processing control. c, Western blots of copper-signalling effectors in AMs from K18-hACE2 mice infected with SARS-CoV-2. Macrophages of several mice were pooled (10 mice per condition). H3 is a sample processing control. d, Average body temperature of mice treated as indicated (n = 6–9 mice per group). e, GO term analysis of downregulated genes in lung tissues of SARS-CoV-2 infected K18-hACE2 mice treated with LCC-12 (0.5 mg/kg). f, RNA-seq analysis of gene expression in lung tissues of SARS-CoV-2-infected K18-hACE2 mice treated with LCC-12 (0.5 mg/kg) (n = 8 mice per group). Inflammatory signature genes highlighted. Dashed lines, adjusted P value = 0.05. g, Illustration of copper-signalling. Cell plasticity involves upregulation of the cell surface marker CD44, which mediates endocytosis of metal-bound hyaluronates. In the presence of copper(II), NADH reacts with H2O2 to replenish NAD+ in mitochondria, an enzyme cofactor involved in the biosynthesis of αKG and acetyl-CoA. These co-substrates of iron-dependent demethylases and acetyl-transferases are required for epigenetic and transcriptional programming of inflammation and the regulation of cell plasticity. Pharmacological inactivation of mitochondrial copper(II) blocks NAD(H) redox cycling, leading to distinct epigenetic states and transcriptional profiles. Targeting copper(II) interferes with cell plasticity in immune and cancer cells. For a – c gating strategy of SPMs and AMs see Methods and Supplementary Information. For d 2-way ANOVA. Mean values ± s.e.m. For e and f differential gene expression was assessed with the limma/voom framework. GO enrichment was assessed with the enrichGO method from clusterProfiler. P-values were corrected for multiple testing with the Benjamini-Hochberg procedure.
