How does emotional stress lead to inflammation?

[Lidia]

It seems widely accepted that “stress” leads to inflammation.

“Stress” in this context is always used to denote emotional stress.

How does emotional stress lead to inflammation? Is there evidence of how this pathway works?

Thanks in advance.

 

[Jonathan Edwards]

It seems widely accepted that “stress” leads to inflammation.

That is not something I recognise as someone who worked in inflammation for 35 years. Who would you think accepts this?

 

[Lidia]

I am so pleased to read your post @Jonathan Edwards. It makes no sense to me. And yet every slightly-less-scientific page I read (web, print, whatever) on inflammation notes that decreasing “stress” (emotional) helps reduce inflammation. I wondered for a long time if I was just not reading the “correct” scientific literature, but now I am thinking it’s not me who is ignorant.

 

[Hutan]

I've wondered about this too.

And yet every slightly-less-scientific page I read (web, print, whatever) on inflammation notes that decreasing “stress” (emotional) helps reduce inflammation.

For example: Healthline

Everyone deals with stress from time to time, and stress can have an effect on more than just your emotional health. Stress can also cause physical symptoms, such as a rash — and having this symptom can amplify your stress.

Many people will experience a stress rash at least once in their lives. Luckily, a stress-induced rash generally isn’t cause for concern. In fact, it can often be treated easily at home.

If you have a preexisting skin condition, such as psoriasis or rosacea, you may also find that stress worsens your symptoms. If this occurs, stress is considered a trigger.

When you’re stressed, it isn’t uncommon to experience a flare-up related to an existing skin condition. This is because your body releases extra chemicals, like neuropeptides and neurotransmitters, when you’re stressed.

These chemicals can change how your body responds to various functions. This change in response can cause inflammation, sensitivity, and other discomfort to the skin.

 

[Alvin]

Since neuroinflammation is one of the many theories as being the cause of depression emotional stress is the missing link.
Thats sarcasm, i don't know if it does and would be surprised if it does.

 

[Hoopoe]

It all began with Hans Selye.

The current usage of the word stress arose out of Selye's 1930s experiments. He started to use the term to refer not just to the agent but to the state of the organism as it responded and adapted to the environment. His theories of a universal non-specific stress response attracted great interest and contention in academic physiology and he undertook extensive research programs and publication efforts.[73]

While the work attracted continued support from advocates of psychosomatic medicine, many in experimental physiology concluded that his concepts were too vague and unmeasurable. During the 1950s, Selye turned away from the laboratory to promote his concept through popular books and lecture tours. He wrote for both non-academic physicians and, in an international bestseller entitled Stress of Life, for the general public.

One of these days I'm going to read the relevant literature. I think it may be possible that these experiments (like Beecher's work on placebo) may have led to misleading or exaggerated conclusions. Because people keep trying to treat disease by treating stress or psychological factors and the results seem to be consistently disappointing.

https://en.wikipedia.org/wiki/Stress_(biology)#History_in_research

 

[Hoopoe]

I think it's correct to say that this began with Selye, even if he focused on the endocrine side of things. Later on other work was done examining cytokine response to stressors and presumably that's where the stress leads to inflammation narrative comes from. My initial feeling (or prejudice), is that this technically correct but probably taken to be more important than it actually is.

So, actually looking for relevant studies, I found this:

Transient responses of inflammatory cytokines in acute stress.

It has been demonstrated that concentrations of pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) are elevated by acute stress. Although several studies confirmed robust changes in IL-6, how acute stress affects other cytokines was less clear. Therefore, the present study simultaneously examined the effects of acute stress on several pro-inflammatory cytokines. Sixteen male participants were given the Trier Social Stress Test (TSST). Blood samples were collected at baseline, immediately after, and 30, 60, and 90min after the TSST. IL-1beta significantly increased immediately after the TSST and returned to the baseline level after 30min. Additionally, this elevation of IL-1beta was correlated with the perceived intensity of stress. These results showed that the concentration of IL-1beta is rapidly regulated, and that elevation of the IL-1beta level could possibly be attributed to transient mobilization of monocytes caused by sympathetic nervous activation. Moreover, a transient increase of IL-1beta might be conveyed to the brain and play a role in forming negative emotional states.

https://www.ncbi.nlm.nih.gov/pubmed/19446599

Looking at this, I wonder if any differences could be explained simply due to differences in exertion. The control group did reading instead which is considerably less demanding than preparing and giving a speech and then doing math. That's a weakness that could invalidate all of their conclusions.

 

[Arnie Pye]

@Jonathan Edwards

I've had eczema on my hands for most of my life. As a teenager at school and a student at university, upcoming exams would send the eczema crazy. Sometimes I could barely bend my fingers, and the skin would crack and bleed if I tried. My fingers were often swollen. Inflammation ran rampant. Once exams were over the inflammation and skin soreness would slowly fade back to my usual level.

I've suspected in recent years that the stress of the exams might have been increasing my cortisol and adrenaline, and that was the source of the worsening of my eczema and the associated inflammation. Is that likely?

 

[Hutan]

This 2012 article
https://www.sciencedaily.com/releases/2012/04/120402162546.htm
suggests

Stress wreaks havoc on the mind and body. Until now, it has not been clear exactly how stress influences disease and health. Now researchers have found that chronic psychological stress is associated with the body losing its ability to regulate the inflammatory response. The research shows for the first time that the effects of psychological stress on the body's ability to regulate inflammation can promote the development and progression of disease.

The proposed mechanism is decreased tissue sensitivity (and specifically immune cells) to cortisol. This is presumably a result of prolonged periods of high cortisol due to chronic stress. Cortisol would normally dampen down inflammation; if cortisol isn't having an effect, inflammation runs amok.

When under stress, cells of the immune system are unable to respond to hormonal control, and consequently, produce levels of inflammation that promote disease.

The link between the two studies mentioned as leading to this conclusion and the conclusion doesn't sound very strong to me.

But, if our problem is inflammation, and if the inflammation is a result of cortisol insensitivity, that would surely be an easy thing to prove?

I'm not too sure how cortisol insensitivity can be responsible for everything from cardiac disease, to asthma, to autoimmune diseases to heightened cold symptoms as well as ME, but only one or some of those diseases in any one person. And why not everyone who has endured, for example, a civil war or a prolonged series of earthquakes develops ME. Is this when we wave our hands around vaguely and say 'genetics'?

 

[Hutan]

Genes Brain Behav. 2007 Mar;6(2):167-76.
Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome.

Link to abstract here

(With apologies to all of you who have lived through this or at least know this already.) This 2007 study with authors including Unger, Vernon and Reeves seemed to find that people with CFS shared polymorphisms of the glucocorticoid receptor gene (NR3C1).

We observed an association of multiple SNPs with chronic fatigue compared to non-fatigued (NF) subjects (P < 0.05)

I haven't read the full text but even in the abstract the HPA axis gets a mention. There were only 40 participants with CFS. I wonder how supported this finding has been in subsequent genetic investigations.

 

[leokitten]

I’ve had psoriasis since I was 18 and any type of stress, physical, mental, or emotional, will likely trigger a flare up if the stressor isn’t short lived. Since getting ME/CFS my psoriasis has gotten worse in every respect and it’s easier to trigger a flare up when there is stress.

Stress is a well known trigger of flare ups in autoimmune disorders. So if this is real then I think your op is totally plausible.

 

[Amw66]

This 2012 article
https://www.sciencedaily.com/releases/2012/04/120402162546.htm
suggests


The proposed mechanism is decreased tissue sensitivity (and specifically immune cells) to cortisol. This is presumably a result of prolonged periods of high cortisol due to chronic stress. Cortisol would normally dampen down inflammation; if cortisol isn't having an effect, inflammation runs amok.



The link between the two studies mentioned as leading to this conclusion and the conclusion doesn't sound very strong to me.

But, if our problem is inflammation, and if the inflammation is a result of cortisol insensitivity, that would surely be an easy thing to prove?

I'm not too sure how cortisol insensitivity can be responsible for everything from cardiac disease, to asthma, to autoimmune diseases to heightened cold symptoms as well as ME, but only one or some of those diseases in any one person. And why not everyone who has endured, for example, a civil war or a prolonged series of earthquakes develops ME. Is this when we wave our hands around vaguely and say 'genetics'?

Dr Bansal was researching glucocorticoid receptor resistance which suggested cortisol resistance. Research has not been published, so i don' t know if it is a null finding @alex3619 was interested in it. Dr Bansal retires from NHS this year. It was explained in the LIME conference in Sweden 2014, which was posted on another thread.

Prolonged fight or flight is not good for anyone, epigenetic changes have been suggested which modulate gut, ( including triggering leaky gut and inflammatory response to LPS) vitamin absorption, blood pressure, glucose metabolism.If the body cannot keep up supply to meet demand then it will impact onto endocrine system , and other systems. I think the argument is that since this response is literally survival instinct that long term exposure to stress rewires things to cope with a dangerous environment- a kind of evolutionary reboot. But our bodies can' t distinguish between stressors so a combination of physical and emotional stress may be more detrimental.

I did a flow chart when my daughter was being bullied to try and understand the effects.i will try and dig it out and you can all tell me where i have gone wrong!

Gene expression ( and the ability to switch this off and on ) may be the difference between developing one illness over another when all other variables are factored in.

Cortisol as far as i know ( i am not scientific) does not have the " nested control" mechanism of other hormones/ compounds, with multiple feedback loops, which may explain why it has such potential to wreak havoc.

 

[Hutan]

Prolonged fight or flight is not good for anyone

True, but surely we would see a massive rise in the incidence of ME in places where the citizens have all undergone a substantial stress if emotional stress was a major factor in ME.

But our bodies can' t distinguish between stressors so a combination of physical and emotional stress may be more detrimental.

True, but my children and I did not have significant emotional stress when we developed ME and the illness that seemed to precipitate the ME was not very severe.

This 2017 review paper by two Australian endocrinologists
https://www.ncbi.nlm.nih.gov/books/NBK279099/
is a bit odd in places and completely wrong in some others. However, it does cover the stress causation theory in great detail with lots of references. I do not understand how the assumption of low cortisol in people with ME prevails when the studies show the majority of PwME have cortisol levels in normal range.

 

[Amw66]

True, but surely we would see a massive rise in the incidence of ME in places where the citizens have all undergone a substantial stress if emotional stress was a major factor in ME.

True, but my children and I did not have significant emotional stress when we developed ME and the illness that seemed to precipitate the ME was not very severe.

This 2017 review paper by two Australian endocrinologists
https://www.ncbi.nlm.nih.gov/books/NBK279099/
is a bit odd in places and completely wrong in some others. However, it does cover the stress causation theory in great detail with lots of references. I do not understand how the assumption of low cortisol in people with ME prevails when the studies show the majority of PwME have cortisol levels in normal range.

I think there are many roads into this illness, which is part of the reason it is so hard to crack.
My daughter's base cortisol is low, so perhaps a subset.

 

[Pechius]

@Jonathan Edwards

I've had eczema on my hands for most of my life. As a teenager at school and a student at university, upcoming exams would send the eczema crazy. Sometimes I could barely bend my fingers, and the skin would crack and bleed if I tried. My fingers were often swollen. Inflammation ran rampant. Once exams were over the inflammation and skin soreness would slowly fade back to my usual level.

I've suspected in recent years that the stress of the exams might have been increasing my cortisol and adrenaline, and that was the source of the worsening of my eczema and the associated inflammation. Is that likely?

The only thing that I'm aware of that is more or less clear (I think) is the connection between stress and mast cells. Not saying that mast cells have something to do with mecfs, but they might. They likely have something to do with eczema and many other skin conditions though.

E.g.: Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor.
or
Mast cells and inflammation

Mast cells can also release pro-inflammatory mediators selectively without degranulation. In particular, IL-1 induces selective release of IL-6, while corticotropin-releasing hormone secreted under stress induces the release of vascular endothelial growth factor. Many inflammatory diseases involve mast cells in cross-talk with T cells, such as atopic dermatitis, psoriasis and multiple sclerosis, which all worsen by stress. How mast cell differential responses are regulated is still unresolved.

But the more interesting thing is that at least in this study, they found that CRF (which is released under stress) does not really lead to MC secretion on it's own, but potentiates it:

Genetic and pharmacologic experiments with murine BMMCs, rat RBL‐2H3, and human LAD2 mast cells demonstrated that although CRF1 activation did not directly induce MC degranulation, CRF1 signaling potentiated the degranulation responses triggered by diverse mast cell stimuli and was associated with enhanced release of Ca2+ from intracellular stores. Taken together, our results revealed a prominent role for CRF1 signaling in mast cells as a positive modulator of stimuli‐induced degranulation and in vivo pathophysiologic responses to immunologic and psychologic stress.

I think it plays quite well into what we see in the real world. Healthy people can handle enormous amounts of stress and have little to no problems, but people who have some kind of susceptibility may react negatively to it.

 

[large donner]

Healthy people can handle enormous amounts of stress and have little to no problems, but people who have some kind of susceptibility may react negatively to it.

Yep, just as people who are non anaphylaxis can eat nuts and non diabetics can eat sugar etc. The mechanism of the disease is not the trigger and the triggers are not the cause.

 

[Webdog]

Even minor distress puts you at risk of chronic disease
https://www.medicalnewstoday.com/articles/322464.php

Dealing with anxiety, depression, and stress at intense levels for a long time can impact our long-term physical health. But what if we are exposed to low levels of psychological distress? Does it still jeopardize our well-being? According to a new study, the answer is "yes."

Alongside Kyle McLachlan, at the University of Edinburgh in the U.K., Prof Gale conducted a study investigating whether exposure to low and moderate psychological distress — which includes symptoms of anxiety and depression — could increase the risk of developing a chronic disease.

 

[large donner]

Alongside Kyle McLachlan, at the University of Edinburgh in the U.K., Prof Gale conducted a study investigating whether exposure to low and moderate psychological distress — which includes symptoms of anxiety and depression — could increase the risk of developing a chronic disease.

So if you diagnose people wrongly with anxiety or depression then they get a later diagnosis of MS or Cancer does that mean the first claim was wrong?

 

[Amw66]

Dr Bansal was researching glucocorticoid receptor resistance which suggested cortisol resistance. Research has not been published, so i don' t know if it is a null finding @alex3619 was interested in it. Dr Bansal retires from NHS this year. It was explained in the LIME conference in Sweden 2014, which was posted on another thread.

Prolonged fight or flight is not good for anyone, epigenetic changes have been suggested which modulate gut, ( including triggering leaky gut and inflammatory response to LPS) vitamin absorption, blood pressure, glucose metabolism.If the body cannot keep up supply to meet demand then it will impact onto endocrine system , and other systems. I think the argument is that since this response is literally survival instinct that long term exposure to stress rewires things to cope with a dangerous environment- a kind of evolutionary reboot. But our bodies can' t distinguish between stressors so a combination of physical and emotional stress may be more detrimental.

I did a flow chart when my daughter was being bullied to try and understand the effects.i will try and dig it out and you can all tell me where i have gone wrong!

Gene expression ( and the ability to switch this off and on ) may be the difference between developing one illness over another when all other variables are factored in.

Cortisol as far as i know ( i am not scientific) does not have the " nested control" mechanism of other hormones/ compounds, with multiple feedback loops, which may explain why it has such potential to wreak havoc.

Flow diagrams - pre ME and scientific paper referencing - screenshots as pdf too large
I was trying to understand the symptoms as they manifest themselves.
I know they are pretty basic - helped me at the time> I find graphics easier to get my head around

 

[Luther Blissett]

Even minor distress puts you at risk of chronic disease
https://www.medicalnewstoday.com/articles/322464.php

So if you diagnose people wrongly with anxiety or depression then they get a later diagnosis of MS or Cancer does that mean the first claim was wrong?

The study is here: https://www.jpsychores.com/article/S0022-3999(18)30047-3/fulltext#back-bb0150

I don't even know how to explain this part:

Socioeconomic position (SEP) was measured at baseline using occupation. Each participant's current job, or most recent job for unemployed participants, was categorised according to Registrar General's Social Class. There were six categories of occupational social class: “professional occupation” [1], ‘managerial and technical occupation’ [2], “skilled non-manual” [3], “skilled manual” [4], “semi-skilled occupation” [5] and “unskilled occupation” [6]. For the purposes of analysing the interaction between distress and SEP, we recoded these occupational classes into two broad categories: 1 = “non-manual” [[1], [2], [3]] and 2 = “manual” [[4], [5], [6]].

That's a lot of messing about to mangle the data into a mess! (They could have used the income data to measure socio-economic position). Their method makes somebody getting unemployment benefits have the same socio-economic position as somebody earning a full wage. Nevermind assuming (wrongly) that the categories have the same socio-economic status differences.

If you assume that an income of £75 per week is the same category as say, £1,000 per week, and that moving from one to the other does not affect your socio-economic status (or amount of stress and anxiety), I don't really know what to say.