Many patients with rheumatoid arthritis are familiar with the pattern: the joints are calm for months, then a particularly stressful phase comes at work or in private life - and a little later the fingers swell again and the pain returns.
The fact that stress can trigger arthritis attacks has long been observed in rheumatology, but has never been satisfactorily explained. One question in particular remained unanswered: Why do some people react to stress with an increase in inflammation, while others hardly react at all?
A new study published in the journal “Science Advances” now provides part of the answer. Their central finding: Joints that were once inflamed seem to remember this inflammation to a certain extent. The connective tissue in the joint mucosa apparently develops a kind of readiness state that reacts much faster and more strongly to a new stressful stimulus than healthy tissue - regardless of whether the classic immune cells are involved.
To understand how this pathway works, it is worth looking at the signaling chain that connects stress and inflammation. When the brain senses a threat—whether a deadline, a conflict, or a frightening thought—it activates the sympathetic nervous system, the branch of the autonomic nervous system that prepares the body for action. This sends signals to, among other things, the brown fatty tissue. This type of tissue, which is found primarily in the neck and shoulder areas, has long been known primarily for its role in heat generation.
Brown fatty tissue responds to stress signals by releasing the messenger substance interleukin-6 into the blood. Interleukin-6 is a so-called cytokine, a signaling protein of the immune system that has far-reaching effects: It is partly responsible for the feeling of exhaustion after stress, can promote itching and plays a role in the development of depressive moods. A previous study had already shown that brown fat tissue functions as a stress-reactive hormonal organ and that interleukin-6 acts as a type of stress hormone.
But what research hasn't been able to explain is why do arthritis flare-ups keep coming back in some patients, even when the disease is clinically in remission? And why do some patients react to stress with violent attacks, while others with comparable illnesses seem to be hardly affected?
For some people, stress alone is enough
Classic rheumatism therapy assumes that acute attacks are mainly triggered by adaptive white blood cells - so-called lymphocytes. In many autoimmune diseases, these incorrectly attack the body's own cells, including rheumatoid arthritis.
The previous expectation was that when arthritis goes into remission, the lymphocytes calm down. And if no new surge is driven by lymphocytes, things remain quiet. Nevertheless, some patients experienced flare-ups even though their therapy – which usually targets lymphocytes – actually works well.
The Japanese research team led by Shigeru Tanaka and Hiroshi Nakajima from Chiba University examined the problem in a mouse model. They first allowed arthritis to transition into a resting phase and then exposed the animals to psychological stress. The result: The inflammation in the joints flared up again. The researchers then tracked which cells and molecules were involved.
They found that the interleukin-6 released via the brown fatty tissue reaches the joints in the bloodstream and meets a specific cell population there: the so-called fibroblasts of the joint mucosa. These connective tissue cells respond to interleukin-6 by releasing another messenger, CXCL1. And it attracts a different type of white blood cell into the joint: neutrophils.
Unlike their learning relatives, the lymphocytes, neutrophils are part of the innate immune system. They are classic inflammatory cells that become active wherever they are called upon in the body. During arthritis attacks, large numbers of them migrate into the joint and release high amounts of inflammatory substances.
What is crucial is what happens in the joints that were once inflamed: their connective tissue cells seem to retain the ability to react to the circulating interleukin-6 and thereby bring in the inflammatory phagocytes - even when the disease is clinically in remission.
The connective tissue in the joint could therefore carry a kind of molecular memory of previous inflammation that can be activated independently of lymphocytes. The cause of recurring arthritis attacks could therefore lie less in the immune system in general than in the effect of stress hormones on the local tissue itself.
Additionally, researchers observed a weaker association between perceived stress and disease activity in some people. These carried a specific genetic variant of the ADRB3 gene, which determines the ability to respond to stress-related hormone signals. This suggests that individual genetic differences in the signaling chain could explain why stress does not trigger attacks of the same magnitude in all arthritis patients.
“Our results suggest that stress-responsive signaling pathways can be used in the future to develop therapies that have a targeted effect - without suppressing the immune system as a whole,” said study author Nakajima in a press release. Obvious points of attack would be both the CXCR2 receptor, through which CXCL1 works, and the ADRB3 receptor in brown adipose tissue.
