How rheumatoid arthritis inflammation spreads between the joints of mice

Rheumatoid arthritis is a chronic inflammatory autoimmune disorder that mainly causes painful joints. It’s estimated to affect over 450,000 Australians.

Remote inflammation is a key feature – where inflammation spreads from one joint to another. Research has shown that factors involved include cells migrating from the joints and neural circuits, but until now the mechanism behind this spread had not been explained.

Now, a new study in mice has found that remote inflammation spreads by neuron crosstalk, and that the molecule adenosine triphosphate (ATP) plays a key role in this by acting as a neurotransmitter and inflammation enhancer.

If the findings are found to apply to rheumatoid arthritis and other chronic inflammatory diseases in humans, they could provide a therapeutic target for various diseases in which inflammation spreads.

The research has been published in the Journal of Experimental Medicine.

Inflammation spreads in rheumatoid arthritis

While short-term acute inflammation is a normal part of the natural immune response to infection or irritation, chronic inflammation can last for periods of several months to years and can cause immune cells to attack healthy tissues.

In rheumatoid arthritis, the immune system attacks the synovial membrane – the tissue lining the joint that produces fluid to lubricate and nourish joint tissues. It becomes thick and inflamed, unwanted tissue growth occurs, and as a result bone erosion and irreversible joint damage can lead to permanent disability.

Using a mice model of rheumatoid arthritis, immunologists investigated whether crosstalk between different types of neurons could be responsible for remote inflammation. They divided the mice into two groups: a control group and a test group where the neural circuits between the left and right ankle joints had been interrupted.

By introducing inflammation into the left ankle, they found that the inflammatory signal in one joint is spread to the other through this neural pathway; interrupting it prevented inflammation forming on the other side.

Specifically, the inflammation signal is spread from sensory neurons (nerve cells activated by sensory input) through interneurons – which transmit signals from sensory neurons to the spinal cord and vice versa.

This led to an increase in ATP in both joints, which in turn triggered an increase of a signalling molecule that resulted in inflammation. So, ATP acts as an intermediary between local inflammation and the neural pathway that induces remote inflammation.

What is adenosine triphosphate exactly?

ATP is a biological molecule essential to all life on Earth because it drives biochemical activity within living cells.

Diagram of the atp and adp cycle. Atp has been found to play a role in the spread of inflammation in rheumatoid arthritis.
The ATP/ADP cycle. Credit: ttsz/Getty Images

ATP is an energy-carrying molecule used by cells to drive metabolic reactions that wouldn’t occur by themselves, to transport substances across cell membranes, and to do mechanical work like moving muscles.

To be clear, ATP doesn’t store chemical energy. Instead, stored chemical energy (from carbohydrates and fats) is converted into ATP, which then delivers that energy to where it’s needed in the cell.

The part of the structure of ATP that acts as this “power source” is the triphosphate tail – a chain of three phosphate groups.

The energy is contained in the bonds between the phosphates and is released when they’re broken; a phosphate group is transferred to another molecule in a process called phosphorylation, and ATP is converted to adenosine diphosphate (ADP).

The 2021 SCINEMA International Science Film Festival animated entry Synthesis of ATP is a stunning visualisation of the cellular process behind making ATP.

In humans, it occurs in the inner membrane of the mitochondria – that’s why they’re known as the powerhouse of the cell – and is carried out by an enzyme complex called ATP synthase. Very simply, ATP synthase catalyses the conversion of ADP and phosphate to ATP, while powered by a difference in proton concentration across the membrane.

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