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Unlocking the Secret of the Spread of Inflammation in Rheumatoid Arthritis: Adenosine Triphosphate (ATP) Is Key

Adenosine triphosphate (ATP) secreted from sensory neuron-interneuron crosstalk acts as an inflammation enhancer and a neurotransmitter, and is mainly responsible for the spread of information from one affected area to another.

According to an analysis of Global Burden of Disease (GBD) data by the World Health Organization, around 14 million people worldwide suffer from rheumatoid arthritis, a chronic autoimmune disorder. It results in remote inflammation of joints, where inflammation spreads from inflamed joints to otherwise healthy joints. Prior research has discovered that this remote inflammation is due to the migration of inflammatory cells to otherwise unaffected sites and neural circuits, but the exact mechanism by which the inflammation spreads has not been discovered.

A collaborative effort between researchers from Japan and the US, led by Professor Masaaki Murakami from Hokkaido University, has led to the discovery that remote inflammation spreads by sensory neuron-interneuron crosstalk, and that adenosine triphosphate (ATP) secreted during the crosstalk plays a crucial role in spreading inflammation in mice. This discovery, published in the Journal for Experimental Medicine, allows for the potential diversification of the approaches for the treatment of inflammatory diseases.

Inflammation is part of the natural immune response fronted by our immune systems to combat infection or irritation by bacteria, viruses, or other foreign contaminants. It involves blood vessels, immune cells, and molecular mediators. This process attempts to eliminate both the pathogens and damaged cells, followed by the repair of any damage. If excessive inflammation occurs for prolonged periods of time, the body’s response may eventually start damaging healthy cells, tissues and organs, increasing the risk of onset of cancer, rheumatoid arthritis, and type II diabetes. Thus, for the maintenance of health, excessive inflammation should be curbed as quickly as possible.

The researchers built upon previous research on the gateway reflex⁠—an immune response where specific neural signals change the state of blood vessels to allow immune cells to enter tissues, leading to inflammation of a specific site⁠—to hypothesise that neural crosstalk could be responsible for the spread of the inflammation. Neural crosstalk refers to the process where one or more components of a signal transduction pathway between neurons affect another transduction pathway.

This hypothesis was tested using rheumatoid arthritis models in mice. Arthritis was induced in the left ankle of mice, and instances of remote inflammation were monitored. In the test groups, the sensory neural circuits connecting the left and the right ankle were disrupted, thus any appearance of remote inflammation in the right ankle would be attributed to the sensory neural circuits.

“Neural circuits between lesions are one mechanism through which local inflammation spreads to remote positions. Here, we show the inflammatory signal on one side of the joint is spread to the other side via sensory neuron–interneuron crosstalk, with ATP at the core. Surgical ablation or pharmacological inhibition of this neural pathway prevented inflammation development on the other side. Mechanistic analysis showed that ATP serves as both a neurotransmitter and an inflammation enhancer, thus acting as an intermediary between the local inflammation and neural pathway that induces inflammation on the other side,” write the investigators.

The results showed that the inflammation signal was indeed transmitted from the inflamed left ankle joint by a sensory neuron circuit that passed through the spinal cord, causing remote inflammation in the right ankle joint. Inflammation in both joints also resulted in increased levels of ATP at both sites, which then induced an increase of another signal molecule that triggers inflammation. In the test case, where the sensory neuron circuit was disrupted, the inflammation remained localised at the left ankle.

However, because these experiments were conducted on mouse models, further investigations would have to be made to confirm that these findings also apply to chronic inflammatory diseases in humans. In that case, it could offer a potential focus for treatment in managing such chronic inflammation conditions. [APBN]

Source: Hasebe et al. (2022). ATP spreads inflammation to other limbs through crosstalk between sensory neurons and interneurons.Journal of Experimental Medicine,219(6), e20212019.