Researchers at the Dublin-based Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences say they have discovered a new way to “put the brakes” on excessive inflammation by regulating a type of white blood cell that is critical for our immune system. The discovery has the potential to protect the body from unchecked damage caused by inflammatory diseases, according to the scientists who published their study “Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages“in Nature Communications.

Macrophages are exposed to potent infectious agents and cytokines are produced to fight the invading infection. However, if these cytokine levels get out of control, significant tissue damage can occur.

The researchers have found that a protein called Arginase-2 works through mitochondria to limit inflammation. Specifically, they have shown for the first time that Arginase-2 is critical for decreasing a potent inflammatory cytokine—Interleukin-1 (IL-1).

This discovery could allow researchers to develop new treatments that target the Arginase-2 protein and protect the body from unchecked damage caused by inflammatory diseases.

“Mitochondria are important regulators of macrophage polarization. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation,” write the investigators.

“We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α), and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2−/− mice.

“These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell.”

“Excessive inflammation is a prominent feature of many diseases such as multiple sclerosis, arthritis and inflammatory bowel diseases. Through our discovery, we may be able to develop novel therapeutics for the treatment of inflammatory disease and ultimately improve the quality of life for people with these conditions,” said senior author on the paper Claire McCoy, PhD, senior lecturer in immunology at RCSI.

The study was led by researchers at the School of Pharmacy and Biomolecular Sciences, RCSI, in collaboration with a network of international researchers from Australia, Germany, and Switzerland.

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