Your body reacts to something that hurts it, like a cut or a germ, by getting inflamed. This means that your body sends out signals, called cytokines, that tell your immune system to get ready. Then, inflammation helps your immune system bring in special cells and other things that can deal with the problem. Inflammation can help your body heal the wound or get rid of the germ.
Inflammation is a vital process that helps the body fight infections and injuries, but sometimes it can last longer than necessary or happen without a clear cause. This is called chronic inflammation, and it can harm healthy cells and organs over time. Chronic inflammation can lead to serious diseases such as heart disease, Alzheimer’s disease, and cancer.
There are few ways to treat chronic inflammation effectively. But a new study in Nature showed a possible way to lower the harmful effects of inflammation.
The study looked at CD44, a protein on the surface of cells that helps them adapt to different environments without changing their DNA. This is important for inflammation because immune cells need to change their behavior to fight infections.
The researchers discovered that macrophages, a type of immune cells that are involved in inflammation, store copper in the mitochondria . Copper, which is found in the energy-producing parts of macrophages, affects inflammation and how the immune system responds.
The researchers created a drug called LCC-12 (also known as “supformin”) using a rational drug design based on a common diabetes drug called metformin. LCC-12 is different from metformin because it only affects the mitochondria, where it blocks copper and stops inflammation. The researchers tested LCC-12 in mice with infections and showed that it lowered inflammation and increased survival.
The study shows how important copper is for controlling cell plasticity, especially the changes in shape that affect inflammation.
What is the effect of copper on the inflammation-inducing state of macrophage ?
According to search published on PubMed Central
Excessive inflammation causes substantial immunopathology. A report in Nature now shows that copper ions promote the metabolic and epigenetic remodelling of macrophages and that copper can be targeted to rein in uncontrolled inflammation.
Solier et al. generated monocyte-derived macrophages (MDMs) from human primary monocytes and found that activated MDMs upregulate the glycoprotein CD44, which is linked to cell plasticity.
CD44 can facilitate the endocytosis of hyaluronan-bound metals including copper, and activated MDMs had higher levels of Cu2+ ions in their mitochondria compared with non-activated MDMs. This was dependent on CD44 and was unaffected by knockdown of other metal transporters.
Whereas known copper chelators had little effect, the antidiabetic drug metformin, which can also interact with copper, interfered with MDM activation. The authors developed a metformin dimer, LCC-12, with an increased capacity to bind Cu2+, that was 1,000 times more potent than metformin in this assay. LCC-12 also inhibited other processes characterized by CD44 upregulation, such as the epithelial–mesenchymal transition of cancer cells.
Cu2+ modulates MDM metabolism by activating hydrogen peroxide, which leads to the oxidation of NADH to NAD+, which, in turn, activates mitochondrial enzymes and causes metabolic reprogramming. This affects the epigenetic regulation of pro-inflammatory genes by promoting the activity of histone demethylases and acetyltransferases.
In mice, intraperitoneal administration of LCC-12 protected against lipopolysaccharide-induced death, increased survival in a sepsis model, and reduced the expression of inflammatory genes in SARS-CoV-2 infection.
Together, these results indicate that CD44 regulates immune cell activation through the uptake of copper. They also highlight the central role of mitochondrial Cu2+ in inflammation, and potentially in cell plasticity in general.
Resources : Frontiersin, E J O P , Nature, F1000RESEARCH, PubMed
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