Researchers discover new way to halt excessive inflammation by targeting Arginase-2

RCSI researchers 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.

The paper, led by researchers at RCSI University of Medicine and Health Sciences, is published in Nature Communications.

When immune cells (white blood cells) in our body called macrophages are exposed to potent infectious agents, powerful inflammatory proteins known as 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 the energy source of macrophage cells, known as mitochondria, to limit inflammation. Specifically they have shown for the first time that Arginase-2 is critical for decreasing a potent inflammatory cytokine called 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.

“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,” commented senior author on the paper Dr. Claire McCoy, Senior Lecturer in Immunology at RCSI.

The study was led by researchers at the School of Pharmacy and Biomolecular Sciences, RCSI (Dr. Claire McCoy, Dr. Jennifer Dowling and Ms Remsha Afzal) in collaboration with a network of international researchers from Australia, Germany, and Switzerland.

The research was funded by Science Foundation Ireland, with initial stages of the research originating from a grant from the National Health Medical Research Council, Australia.

Macrophages are important immune cells that can exert either pro-inflammatory or anti-inflammatory functions, for innate as well as adaptive immune responses1. Metabolically, it has been shown that in vitro ‘M1-like’ inflammatory macrophages utilize aerobic glycolysis for the generation of ATP.

This is accompanied with a downregulation of mitochondrial oxidative phosphorylation (OxPhos) and an accumulation of certain metabolites in the tricarboxylic acid (TCA) cycle, such as citrate and succinate2,3. Conversely, diverse anti-inflammatory stimuli including IL-10, IL-4, and IL-13 are ‘M2-like’ anti-inflammatory phenotype inducers.

M2-like cells are shown to favour the use of OxPhos4,5, which has been linked to specific alterations in macrophage mitochondrial dynamics6,7,8.

IL-10 is an anti-inflammatory cytokine acting in an autocrine fashion in macrophages to limit inflammatory responses by decreasing the production of pro-inflammatory cytokines9,10. Simultaneously, IL-10 increases anti-inflammatory genes, typically in a STAT3 dependent manner10,11,12,13.

Furthermore, inflammatory macrophages utilize arginine for the production of nitric oxide (NO), which IL-10 can limit by inhibiting the transcription of inducible nitric oxide synthase mRNA (Nos2)14,15 or by enhancing the degradation of iNOS protein10,16. Concomitantly, IL-10 increases arginase expression to limit the availability of arginine for NO production13,17.

In fact, IL-10 was shown to regulate macrophage glycolytic commitment by preserving OxPhos through its suppression of NO18 or via suppression of mammalian target of rapamycin (mTOR)19. It has also been shown that IL-10, via STAT3, inhibits the pro-inflammatory microRNA miR-15520. IL-10 was shown to modulate miR-155 target genes suggesting a distinct mechanism that IL-10 uses to maintain an anti-inflammatory state in macrophages20.

Here, we identify Arg2 as one of the most prominent metabolic genes regulated by the IL-10/miR-155 axis. We also show that IL-10-mediated induction of Arg2 protein is essential for skewing mitochondrial dynamics and bioenergetics in inflammatory macrophages towards an oxidative phenotype, particularly by enhancing activity of complex II (CII) at the electron transport chain (ETC). This work highlights Arg2 as a downstream mediator of IL-10 and provides a mechanism for its function as a resolver of inflammation.

reference link: https://www.nature.com/articles/s41467-021-21617-2

More information: Nature Communications (2021). DOI: 10.1038/s41467-021-21617-2