While some problems simply need a Deerstalker and a helpful sidekick to solve, discovering the cellular processes controlling inflammation has been less of an “element-ary” task! Now, an epigenetic study (in Scarlet?) links inflammation to a mechanism involving a membrane protein, the uptake of copper, and histone modifications in macrophages!
A team of epigenetic investigators led by lead detective Raphaël Rodriguez (Institut Curie, Paris, France) sought to explore the roots of inflammation and identify therapeutic approaches to reduce tissue injury and organ failure by focusing on the cell surface glycoprotein CD44, which mediates the endocytosis of iron-bound hyaluronates. Iron activates the α-ketoglutarate-dependent demethylases involved in gene expression regulation, while hyaluronates induce the expression of pro-inflammatory cytokines in macrophages, whose activation relies on epigenetic mechanisms. Therefore, can CD44-mediated metal uptake activate inflammatory macrophages through an epigenetic mechanism? Element-ary, dear reader!
Let’s hear more about this Sherlockian piece of detective work from Solier, Müller, Cañeque, Versini, and Colleagues:
- Among other metals, upregulated CD44 expression in inflammatory human monocyte-derived macrophages prompts an increase in copper levels in mitochondria
- Copper catalyzes NAD(H) redox cycling by activating hydrogen peroxide to prompt a reduction in the levels of α-ketoglutarate and acetyl-coenzyme A, which control the turnover of iron-dependent demethylases and acetyltransferases that directly impact histone modification patterns
- Increases in H3K27ac, H3K14ac, and H3K9ac and reductions in H3K27me3 and H3K9me2 at gene regulatory regions then drive the expression of inflammation-associated genes
- Supformin – a rationally-designed dimer of the copper-binding drug metformin – exhibits improved biological and preclinical characteristics and supports the targeted inactivation of mitochondrial copper
- Supformin treatment reverses the inflammation-associated histone modification and transcriptional alterations in macrophages as a means to reduce unwanted side effects of the inflammatory process
- Supformin confers therapeutic benefits in well-established mouse models of acute inflammation by altering the above-noted histone modifications (all characterized by upregulated CD44 and increased cellular copper)
- Supformin also interferes with the epithelial to mesenchymal transition of metastatic cancer cells, supporting a broader role for CD44/copper in the epigenetic regulation of transcription associated with disease
Rather than twiddling their thumbs or causing a scandal, this dogged team of tweed-bedecked epigenetic investigators made a rather element-ary finding – that CD44-mediated copper uptake by macrophages creates metabolites that modify histone modification profiles to induce inflammation. Furthermore, they identified a potential therapeutic means of reducing the unwanted consequences of prolonged inflammation, which may also have relevance in cancer treatment.
Lead author Raphaël Rodriguez concludes: “Our study reveals that the inflammatory and cancer processes depend on similar molecular mechanisms and could therefore in the future benefit from similar innovative therapies, such as those tested with Supformin.”
To read more on this compelling yet element-ary case of epigenetic intrigue, see Nature, April 2023.