It’s winter time and it’s getting cold outside. Your skin becomes dry and starts to feel irritated. All you really want to do is scratch it!  The reasons behind the itch sensation are surprisingly complicated. It involves interplay between the immune system and the nervous system, arguably the two most complex systems in the body.  We experience this phenomenon when bitten by an insect, exposed to an irritant and if you unfortunately suffer from an allergic skin disease.

In a recent study, clusters of sensory nerves and immune cells located within the skin were found to play an important role in the development of allergic skin diseases.  When exposed to allergens like house dust mites the sensory nerves became activated and initiated a conversation with local immune cells. This process is called “neuro-immune crosstalk” and occurs when chemicals produced by the sensory nerves stimulate the neighboring immune cells. Once stimulated the immune cells mount an allergic response resulting in allergic skin disease symptoms.

The research team believe that these “neuro-immune clusters” act as sensors to allergens from the outside environment and may play an important role in the development of other allergic conditions like asthma. Identifying the chain of events that occur between the nervous system and the immune system when exposed to house dust mites opens up for the discovery of novel drug targets to prevent allergic responses.

What is atopic dermatitis?

Approximately 30% of individuals in the USA and Australasia experience atopic dermatitis, commonly known as eczema, during their lifespan. Eczema is a non-contagious inflammatory skin condition where the skin is ‘hypersensitive’ to environmental triggers such as pollen, mold and house dust mites. It is characterized by severe itching of red and dry skin and the formation of lesions, making individuals prone to skin infections and suffering from discomfort. Eczema often appears in childhood and has been linked to the development of other allergic conditions like asthma, hay fever and food allergies.

The causes or triggers of eczema are not well understood. Genetics, environmental factors, and skin structure and integrity are thought to all impact skin lesion development and severity in eczema.

The skin landscape

There are many different components which make up the skin. This study focuses on the interplay between immune cells, which act as our first line of defense against infections, and a network of sensory nerves called ‘Nociceptors’. These nerves can detect temperature, pain and itch, and transmit nerve signals to induce behavioral responses. For example, these nerves induce scratching when exposed to an irritant or cause you to rapidly move your hand away from a hot surface. Nociceptors produce a chemical called neuropeptide SP, a potent neurotransmitter found in many locations around the body including the brain, spinal cord and gastrointestinal tract. Previous clinical studies have shown that eczema patients have high amounts of neuropeptide SP circulating in their blood.  However, the connection between neuropeptide SP and eczema remains unclear.

In eczema skin lesions there is an increased number of activated innate immune system cells called mast cells and eosinophils. These cells are important in fighting invading microorganisms, however they also initiate allergic responses.  These cells release histamines and other chemicals which promote inflammation and can also communicate with local nerves. If you suffer from hay fever, you will be very familiar with the actions of histamines. They cause widening of blood vessels allowing for other immune cells to move to the area, constriction of muscles and the secretion of mucus to expel the allergen or microorganisms.

As nociceptors promote scratching behavior, probably through the release of neuropeptide SP, the researchers asked the question: do these nerves communicate with mast cells to drive the development of allergic skin diseases?

A laboratory model of allergic skin inflammation 

To investigate the link between the nervous and immune systems in the development of eczema, the team used a mouse model of allergic skin inflammation.

Most eczema sufferers are colonized with a bacterium called Staphylococcus aureus. Those colonized with a strain which produces a toxin called staphylococcal enterotoxins B (SEB) experience severe symptoms. Using this information, the scientists treated mice with a combination of SEB and Dermatophagoides farinae, a house dust mite, to generate symptoms of skin inflammation. Similarly to what is observed in eczema patients who are colonized with Staphylococcus aureus, mice treated with bacterial toxin SEB and house dust mites experience severe symptoms of skin inflammation.

With this laboratory model of allergic skin inflammation, the scientists were able to investigate the role of the different components of the nervous and immune systems in the development of eczema.

The first piece of the puzzle – nerves and neuropeptides

As mentioned earlier eczema patients have high levels of neuropeptide SP circulating in their blood.  The scientists first wanted to figure out how neuropeptide SP fits into the picture and started by identifying TRPV1+ nociceptors, unique nociceptors that produce neuropeptide SP. Using their mouse model of allergic skin inflammation, the scientists compared allergic symptoms after treatment with bacterial SEB toxin and dust mites in normal wild-type mice (WT) to mice that can’t make neuropeptide SP.  They found that WT mice developed clinical symptoms of eczema including skin lesions and antibodies against dust mites in the blood.  However, the mice without neuropeptide SP did not experience symptoms, demonstrating that neuropeptide SP plays an important role in the development of allergic skin inflammation.

The next piece of the puzzle- dust mites and nociceptors

Next, the scientists tested if and how dust mites were being detected by the nociceptors.  They did this by performing ex vivo experiments, where nociceptors were grown in a dish in the laboratory. When the scientists added dust mites to the dish, the neurons responded by producing and releasing neuropeptide SP. This experiment showed that dust mites were directly stimulating nociceptors.

 

But how do dust mites get on your nerves?

Like other house dust mite types, the researchers found that D. farinae (the type of dust mite used in this study) has enzyme proteins called ‘cysteine proteases,’ which are thought to be involved in digestion. These enzymes are often detected at high levels in dust mite faecal pellets and can break down junctions at the barriers between two neighboring skin cells. This action allows allergens to penetrate the skin where the allergic immune response begins.

To test if these enzymes were activating nociceptors, the scientists treated dust mite extracts with drugs that inhibit the cysteine proteases or treated the extracts at a high temperature to stop the enzymes from working. When the treated extracts were added to the dish containing nociceptors, the neurons could not be stimulated anymore. This demonstrated that the digestive enzymes of dust mites are important for activating the nociceptors.

The team went on to test if other known allergens could activate nociceptors, including another house dust mite strain called D. pteronyssinus (which also has cysteine proteases), Ragweed pollen, Alternaria alternata (a fungus) and German cockroach (these latter three use a different enzyme). They found that only the other house dust mite strain (D. pteronyssinus) could directly activate the nociceptors, highlighting that allergens with cysteine protease enzymes are specifically activating these nerves.

The final piece of the puzzle – stimulating the immune response

In the lesions of allergic skin inflammation, mast cell numbers are elevated.  During an allergic response, mast cells undergo ‘degranulation’, which is the release of stored chemicals like histamines into the surrounding environment.  In this study, the scientists identified an important type of mast cell in the skin which expresses a receptor that can bind to neuropeptide SP. Could this be the final piece of the puzzle?

The answer is yes!  Using high precision microscopes, the scientists were able to visualize the degranulation of mast cells after local nociceptors were activated with dust mites and bacterial toxin SEB. After closer examination they also discovered that location was very important and identified “neuro-immune clusters” where many mast cells were in direct contact or in close proximity with dust mite-activated nociceptors.

Neuro-immune clusters make you scratch that itch

Starting with the detection of dust mite allergen by the sensory neurons in the skin to the initiation of the allergic immune response, this study identified a series of elaborate steps linking the nervous and immune systems in the skin. The researchers discovered “neuro-immune clusters” which act as sensors to detect allergens from the external environment.  It is possible that these are found in other locations around the body, such as the lung and nose, which are significant sites for other allergic diseases including asthma.  The knowledge from this study could help identify new drug targets to prevent the allergic response. For example, instead of using anti-histamines, which block the activity of histamines, interactions between neuropeptide SP and mast cells could be an alternative and earlier drug target.

 

Journal Article: Serhan, N., Basso, L., Sibilano, R. et al. House dust mites activate nociceptor–mast cell clusters to drive type 2 skin inflammation. Nature Immunology 20, 1435–1443 (2019). https://www.nature.com/articles/s41590-019-0493-z

Cover Image: ‘A scanning electron micrograph of a female dust mite’ photographed by Matt Colloff. Available at CSIRO Science Image and is licensed under CC BY 3.0.

Figures created with BioRender