Glucocorticoids (GCs) are potent anti-inflammatory drugs widely used to treat various diseases related to the immune system: rheumatoid arthritis, inflammatory bowel disease and asthma. However, long-term use of GCs is associated with severe side effects, including an increased risk of infections, insulin resistance, and osteoporosis. By studying exactly how glucocorticoids work, new treatment strategies could be developed that could take advantage of the anti-inflammatory properties of glucocorticoids without the associated side effects.
Glucocorticoids: Mechanism of Action
Glucocorticoids act by binding to the glucocorticoid receptor in cells, which, upon activation, translocates to the nucleus and regulates the activity of specific genes. This helps control inflammatory processes in the body. However, not all effects of glucocorticoids are explained by their ability to activate genes. Some anti-inflammatory effects of glucocorticoids occur due to blocking specific signaling molecules, allowing glucocorticoids to suppress the inflammatory response.
Scientists from the German Center for Immunotherapy (DZI) discovered that glucocorticoids affect cell energy production and suppress inflammatory gene activity.
How Cells Generate Energy: Krebs Cycle
The Krebs cycle, which occurs in the mitochondria – the cell’s energy powerhouses, plays an essential role in energy production. During the Krebs cycle, carbon dioxide and water are produced from acetyl-CoA, and electrons are released. These electrons are then used to synthesize adenosine triphosphate (ATP) in oxidative phosphorylation, also known as mitochondrial respiration. ATP is a universal energy source for many cellular functions, including amino acid synthesis and signal transduction.
Pyruvate is required to initiate the Krebs cycle. This molecule is formed as a result of glucose breakdown. After pyruvate is formed, it is transported into the mitochondria and converted into acetyl-CoA, which initiates the Krebs cycle.
Glucocorticoids Increase Energy Production in Macrophages
Scientists from the DZI investigated how glucocorticoids affect macrophages – cells of the innate immune system. Macrophages were activated using lipopolysaccharide (LPS), commonly used to simulate infection. After treatment of activated macrophages with glucocorticoids, it was found that:
- GCs do not broadly suppress the activity of inflammatory genes but act selectively, and their action depends on time. GCs partially block the initial inflammatory response and affect the activity of NF-κB and AP-1 proteins, which regulate gene activity.
- GCs influence macrophage metabolic pathways – they stimulate mitochondrial respiration and pyruvate metabolism. GCs enhance pyruvate consumption in the Krebs cycle, increasing macrophage energy production.
- GC treatment also led to an increase in the volume of mitochondria in LPS-activated macrophages.
Metabolic Changes in Macrophages Are Necessary for the Anti-inflammatory Effect of Glucocorticoids
Enhanced pyruvate metabolism and mitochondrial respiration in macrophages are necessary for the anti-inflammatory action of GCs. Blocking the Krebs cycle under conditions of low oxygen content or with specific inhibitors led to the loss of the anti-inflammatory effect of glucocorticoids.
The Anti-inflammatory Action of Glucocorticoids Depends on Itaconate – a Metabolite of the Krebs Cycle
Glucocorticoids induce metabolic changes in macrophages, enhancing Krebs cycle activity and increasing itaconate production–a metabolite with potent anti-inflammatory properties. Itaconate suppresses the production of pro-inflammatory cytokines IL-1β, IL-6, and TNF.
Itaconate is necessary to suppress inflammation in response to GCs. In experiments with macrophages from mice lacking the Acod1 gene, which is required for itaconate production, GCs were less effective in suppressing the production of pro-inflammatory cytokines. However, adding itaconate mimetics restored the anti-inflammatory effects of GCs. Experiments on human cells also showed that suppressing the activity of the ACOD1 enzyme reduces the anti-inflammatory effect of GCs.
The success of glucocorticoid treatment depends on the activity of the ACOD1 enzyme.
GCs in Lung Inflammation
In an experiment on mice, glucocorticoids successfully prevented lung inflammation induced by LPS exposure. However, GCs were effective only in normal mice, not in mice deficient in the ACOD1 enzyme involved in itaconate synthesis.
GCs in Rheumatoid Arthritis
In patients with rheumatoid arthritis receiving GCs, the level of itaconate in the blood was higher, indicating its essential therapeutic role. Experiments on mice with arthritis confirmed that GCs significantly improved the condition of the mice by increasing the level of itaconate. However, in the absence of ACOD1, the treatment was ineffective.
GCs in Asthma
In mice with allergic airway inflammation, GCs reduced allergic reactions and decreased immune infiltration in the lungs. However, in mice lacking ACOD1, GC treatment did not lead to improvement.
Conclusion
The success of glucocorticoid treatment depends on their ability to change cells’ metabolic profile, particularly by increasing itaconate production – a metabolite that suppresses the production of pro-inflammatory cytokines. Itaconate is essential for the anti-inflammatory action of GCs in conditions such as rheumatoid arthritis and asthma.
Side effects of prolonged glucocorticoid use, such as increased fat mass and development of diabetes, may be associated not only with the effects of GCs on gene activity but also with changes in mitochondrial metabolism. Understanding these processes could aid in developing new anti-inflammatory drugs without serious side effects.
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Reference
Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids
