Key to spreading inflammation in rheumatoid arthritis found

Rheumatoid arthritis is a chronic inflammatory autoimmune disease that primarily causes joint pain. It is estimated to affect over 450,000 Australians.

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

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

If the findings turn out 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 was published in 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 tissue.

In rheumatoid arthritis, the immune system attacks the synovial membrane, the tissue that lines the joint that produces fluid to lubricate and nourish the 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 mouse 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 in which the neural circuitry between the left and right ankle joints had been disrupted.

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

In particular, the inflammation signal is spread by sensory neurons (nerve cells activated by sensory inputs) through the 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 in a signaling molecule that resulted in inflammation. Hence, ATP acts as an intermediary between local inflammation and the neural pathway that induces remote inflammation.

What exactly is adenosine triphosphate?

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

The ATP / ADP cycle. Credit: ttsz / Getty Images

ATP is an energy-carrying molecule used by cells to drive metabolic reactions that would not occur on their own, to carry substances across cell membranes, and to perform mechanical jobs such as moving muscles.

To be clear, ATP does not store chemical energy. Instead, the chemical energy stored (from carbohydrates and fats) is converted into ATP, which then provides that energy where it is needed in the cell.

The part of the ATP structure that acts as an “energy source” is the triphosphate tail, a chain of three phosphate groups.

Energy is contained in the bonds between phosphates and is released when they break; a phosphate group is transferred to another molecule in a process called phosphorylation and the ATP is converted into adenosine diphosphate (ADP).

The animated voice of the 2021 SCIEMA International Science Film Festival Synthesis of ATP is a stunning visualization of the cellular process behind ATP production.

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

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