As a researcher specializing in medical genetics and a fervent advocate for rare diseases, I frequently confront the unbearable challenges faced by patients with debilitating conditions such as muscular dystrophy (MD) and fibrodysplasia ossificans progressiva (FOP)—both of which involve significant inflammatory processes. These diseases not only complicate management but also severely impact quality of life. A common therapeutic recommendation involves glucocorticoids, such as dexamethasone or prednisolone. Although these steroids are far from curative, they play a crucial role in managing symptoms and enhancing patient comfort. Having been prescribed steroids myself, I have firsthand experience with their effects. While effective, glucocorticoids are a double-edged sword—providing relief but also bringing significant side effects that complicate long-term management strategies. Despite these challenges, they remain essential in our arsenal against these incurable diseases. But what is the mechanism behind their action? Honestly, we do not have a good answer to this question.
A recent study published in Nature a couple of days ago suggests a potentially revolutionary approach that could allow us to maximize the benefits of glucocorticoids while minimizing their adverse effects. Traditionally, glucocorticoids have been understood to modulate inflammation through the glucocorticoid receptor (GR), influencing gene expression. This mechanism, while effective, is also associated with several complications, e.g., increased fat mass and a heightened risk of type 2 diabetes. However, J.P. Auger and G. Krönke, the lead scientists of the study, introduce a lesser-known pathway involving rapid changes in cellular metabolism, particularly through the enhancement of the tricarboxylic acid (TCA, also known as Krebs' cycle) cycle in macrophages, leading to the production of itaconate—a metabolite with potent anti-inflammatory properties. They demonstrate that glucocorticoids do more than just modify gene expression; they profoundly alter cellular metabolism, especially in mitochondria, the cellular powerhouses. By boosting the TCA cycle, glucocorticoids increase the production of itaconate, which does not require the extensive gene regulation traditionally associated with glucocorticoid action. The pivotal role of itaconate in quickly and sustainably reducing inflammation suggests it is central to the immediate therapeutic effects of glucocorticoids. Importantly, the anti-inflammatory effects mediated by itaconate do not rely heavily on the GR-mediated transcriptional response, indicating a potential to design steroid therapies that activate the beneficial effects of itaconate without initiating the broader, often harmful, genetic responses typically induced by GR activation.
Figure: Traditional and recent insights into glucocorticoid action. On the left, the traditional pathway shows glucocorticoids acting through the glucocorticoid receptor (GR), leading to gene expression modulation and subsequent anti-inflammatory and immunosuppressive effects. On the right, the new pathway demonstrates how glucocorticoids can enhance the TCA cycle, increase itaconate production in macrophages, and mediate anti-inflammatory effects through itaconate. This illustrates the role of glucocorticoids in reprogramming the metabolism of immune cells to activate the body's natural 'braking system' on inflammation, contrasting with the traditional view that they cause transcriptional changes to suppress the body's inflammatory response.
These findings could be transformative for patients with chronic conditions like MD and FOP, where inflammation plays a critical role. The possibility of decoupling glucocorticoids' anti-inflammatory properties from their metabolic and systemic side effects could lead to more targeted and safer inflammation management, potentially enhancing treatment compliance and outcomes. The path to integrating these findings into practical treatments will require extensive clinical testing and development. However, the prospect of developing glucocorticoid therapies that specifically enhance itaconate production without extensive GR activation is an exciting and promising avenue of research.
The implications of this excellent study extend beyond the laboratory into the consultation rooms where we meet and treat our patients. For those working on the front lines of treating currently incurable disorders that directly or indirectly involve inflammation, any development that can provide effective relief without the burden of side effects holds the promise of better management and potentially transformative care. As this research progresses, I remain hopeful and actively engaged, looking forward to the possibilities these new insights may bring to clinical practices, ultimately improving the lives of those affected by these challenging conditions.
13 April 2024
Saeed Anwar
Edmonton, Canada