July 2019

What would you ask your cells if they could talk?

Imagine your cells could talk, a weird thought I know but stick with me. What would you ask them? One thing we all want to know, skin condition or not, is why do I itch? Good news. Here to try and answer that itching question (see what I did there?) are three key cells from an itchy body. The extracts from their letters dispel some of the myths about itching and give insights into how ongoing research is shaping new treatments.

Letter from a mast cell

The scientists always blamed my histamine. The endless antihistamines worked some of the time but honestly, do they think that’s all I’ve got? When I’m faced with something I don’t like, I degranulate and this spells disaster! My granules are brimming, you see, with what I like to call pruritogens. Histamine is one, of course, but I carry too many to name. Those pesky scientists have started to clock on, developed an interest in tryptase, my trusty protein eating machines. Anyway, I’m not taking all the blame. There are lots of cells that release pruritogens: the keratinocytes, the immune cells. Give me a break man!

Mast cells have long been thought to be the route of all evil. In allergic individuals, mast cells degranulate when they recognise an allergen such as pollen. Histamine is released and does cause itching, but scientists are becoming aware of many more pruritogens including the enzyme tryptase1. In patients with atopic dermatitis, there is an increase in expression of tryptase and its receptor PAR-2 on nerve endings2. Likewise, we now know that other cells can release pruritogens and cause itching. Once pruritogens have been release, it’s down to the nervous system to take over. Let’s hear from a nerve fibre and see what she has to say for herself.

Degranulate When cells release molecules stored in vesicles (granules)

Pruritogen = A fancy word for a substance that make you itch.

Letter from a C nerve fibre

Once you’ve irritated me, there is no turning back. We, the C fibres, are the ones that react to whatever the mast cell releases and to reiterate, most of us couldn’t care less about histamine. In fact 90% of us are histamine unresponsive3! How about that! What ever it is that stimulates our receptors, the electric potential builds up until we just… can’t… take it and BAM, a nerve impulse is sent shooting to the brain! I apologise on our behalf, but you must understand, we are trained that way. As far as we know, pruritogens mean danger so we really can’t be blamed.

As our nerve fibre explained, the next stage of an itch is the detection of the pruritogen. This stimulates free nerve endings in the skin through receptors. In the dermis are histamine-sensitive C fibre neurones that detect histamine on H1 receptors. In the epidermis are the more abundant histamine-insensitive fibres that detect pruritogens like tryptase on PAR-2 receptors. For both, activation of their receptors leads to a build up of charge and once above threshold, nerve impulses are sent along the fibre.

The resistance of many forms of itch to antihistamines is an ongoing clinical problem. It has prompted research into non-histaminergic pathways of itch in the hope that we can develop alternative treatments. Mucuna pruriens is a tropical legume cultivated in parts of Africa and Asia. In Nigeria, the plant has been named ‘The Devil’s Bean’, owing to the intense itch caused by skin contact. The hairs of the seedpods contain cowhage, an external pruritogen that acts like tryptase through PAR-2. In 2007, Davidson et al examined the responses of primate neurones to histamine and cowhage and found that they never activated the same cell3. In other words, there are separate itch pathways for each pruritogen which means blocking histamine will have no effect on these types of itches. But why do we feel the itch? On to the brain for the last part of the story.

Epidermis = Outer most layer of the skin containing flattened cells

Dermis = The thick layer of tissue below the epidermis containing blood vessels and sweat glands etc

C-fibre neurones = Unmethylated and thin nerve cells with a slow conduction velocity

Letter from a brain cell

The C-fibres have been sending itch signals racing down the spinal highway and wreaking havoc throughout the cerebral cortex. No wonder we can’t focus on anything else! The sensory areas decode where the itch is and its intensity. But motor areas are also stimulated to get us ready to scratch and the prefrontal cortex is responsible for that irresistible urge. Most of all, when we do give in and scratch, the reward circuits set loose and ahh the relief. The itch never stays away for long though, and it always comes back worse than before. Woe is me.

Poor brain. MRI and imaging studies of the brain following exposure to pruritogens shows no single part is responsible for the experience of itching. Interestingly, the premotor area that prepares the scratch is activated ‘contralaterally2. This means that an itch on the left arm activates a scratching motion by the right hand and visa versa which shows just how intricate the system is.

But why such a drive to scratch when everyone knows it makes it worse? Scratching evolved as an important protective mechanism to remove potentially harmful triggers like mites from the skin. However, in the context of skin disease, pruritogens may be generated due to something like pollen or skin damage itself. In this case, scratching only causes more skin damage releasing more pruritogens and triggering a vicious cycle of itch-scratch. Treating the itch, even if its source is unknown, is thus of value. In controlled clinical settings, coolants and local anaesthetics may be used to reduce transmission of itchy signals the brain, helping to manage further skin damage4. Furthermore, non-invasive brain interventions to target itch circuits in the brain, such as psychological treatments, have shown potential in conditions such as atopic dermatitis5.

Contralateral = Opposite side

In conclusion, the letters from some of the cells involved in itching have helped us to understand why we itch. There is still a lot to learn. Scientists are discovering more about non-histaminergic pathways, research which will help us develop topical treatments besides antihistamines. We also know more abut the brain areas responsible, opening doors to neural therapies. If you’re interested in getting into the nitty gritty science, have a look at some of the studies referred to in this article.

Likewise, the British Skin Foundation funds a number of important research projects and your support is welcomed.  

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Shannon Guild, University of Oxford Biomedical Sciences

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  1. Joice, R. et al. NIH Public Access. 6, 1–16 (2014).
  2. Brennan, F. & Hospital, S. G. The pathophysiology of pruritus – A review for clinicians. 24, 133–146 (2016).
  3. Davidson, S. et al. NIH Public Access. 27, 10007–10014 (2010).
  4. Song, J. et al. Pruritus : Progress toward Pathogenesis and Treatment. 2018, (2018).
  5. Mochizuki, H., Schut, C., Nattkemper, L. A. & Yosipovitch, G. Allergology International Brain mechanism of itch in atopic dermatitis and its possible alteration through non-invasive treatments. Allergol. Int. 66, 14–21 (2017).