Genetic Frontiers in our Understanding of Eczema

By Monica Enamandram, MD

Itching is one of the hallmark symptoms of a number of skin diseases. Chronic itch can cause substantial suffering and unfortunately affects millions of Americans. Although a variety of treatments are available for itch, nonetheless this symptom can be difficult to treat for both patients and providers. A significant clinical and research interest in dermatology is aimed at understanding the molecular basis of this process. Through genetic mouse models, mammalian studies, microneurography and other studies, recent advances have helped identify the mediators of itch. These have led to insights that are continuing to advance our understanding of this complex process.

This June, an exciting development in this field emerged as a result of a study performed by scientists in the Buck Institute for Research on Aging and the University of California, Berkeley, published in the early online version of the journal Neuron. Through collaboration between Diana Bautista PhD, Rachel Brem PhD, and colleagues, the study identified a serotonin receptor (HTR7) as a key mediator of itch. To begin this discussion, the first sections of this article will detail our understanding of the biology and mechanism of itching. After providing this framework, the second section of this article will shift to describe this groundbreaking work published in Neuron, and its clinical implications for atopic dermatitis.

The diversity of itching

The phenomenon of itching, known as pruritus, can be subdivided into one of four clinical categories. Neurogenic itch refers to a process that is generated in the central nervous system in response to pruritogens (substances that elicit an itch and the urge to scratch in the skin) but without underlying abnormalities of the nerves themselves. Conversely, psychogenic itch is derived from a psychological disorder. The third subtype, neuropathic itch, is complex and thought to be derived from neuronal dam- age or dysfunction that can result in itch in the absence of noxious stimuli. This type of itch may be accompanied by other abnormalities of sensation, such as numbness, tingling, or excessive physical sensitivity of the skin.

Finally, pruritoceptive itch is the fourth subtype of itch, which is one of the most common symptoms experienced by patients who present to the dermatology office. This process originates in the skin owing to either inflammation and/or skin damage. Inflammation can occur following a number of potential internal stimuli or external exposures (such as dust, clothing fabrics or bugs), which produces itch.

Regardless of the origin of an itch, a universal behavior results. As soon as we feel an itch, our first natural response is to scratch the affected area. The reason for this response is simple — we want to remove the irritant as soon as possible.

The biological underpinnings of itch

There are two theories as to how pruritoceptive itch is transmitted from the skin to the brain. The first, the “labeled line” theory suggests that there are itch-specific nerve fibers. These fibers are thought to extend through one or more connections in a circuit that begins in the skin and transmits to the spinal cord, and ultimately to the central nervous system.

The second “selectivity theory” posits that there are nerve fibers that send itching signals to the brain, which are also responsible for transmitting pain signals. Itching and pain, interestingly, share a number of commonalities. For example, the neurologic pathway that transmits both of these sensations in the spinal cord is shared, known as the spinothalamic tract. Brain areas activated by pruritus have also been implicated in the processing of pain in the central nervous system.

According to the selectivity theory, a specialized population of nerve fibers exists in the skin, the majority of which will only respond to pain. Yet a select subset exists that can respond to both itch and pain. The pain-related nerves are thought to inhibit the itch-sensitive nerve fibers. Therefore itch can occur only when itch-sensitive nerve fibers are selectively activated. In other words, if a stimulus triggers both itch- and pain-sensitive nerve fibers then the sensation of pain will predominate, masking the itch. This theory is supported by the observation that severe pain and itch are not simultaneously perceived. Moreover, the notion of pain as an inhibitor of itch can be translated to the fact that we can soothe an itch through scratching (theoretically triggering pain perception).

Various pruritogens interact with molecular detectors in the skin, which can be found on nerve fibers of the skin and cells in the superficial layer of the skin (epidermis) known as keratinocytes. These molecular detectors set off a cascade of events to transmit an itch signal. Their mechanisms are diverse and have attracted ongoing interest as potential drug targets to treat itch. For example, ion channels are a type of molecular detector that have been shown to transmit signals related to itch – among ion channels, the transient receptor potential (TRP) family has been extensively studied and shown to have an important role in certain pathways that transmit pruritoceptive itch.

New developments in an exciting field

Owing to a rapidly growing body of research, the field of itch has significantly expanded in recent years. Scientists have discovered a number of mediators that are thought to play a role in pruritoceptive itch. Histamine classically has been associated with this type of itching. Yet the fact that antihistamines are sometimes only a partially effective treatment is well recognized. This among other reasons led to the investigation of other mediators that could be potential drivers of these distressing symptoms.

Substances that are independent of histamine such as tryptase, cowhage, cathepsin S, kallikreins, cockroach and dust mite protease allergens have been shown to stimulate itch via a molecular detector known as protease-activated receptor-2 (PAR2). Other immune system-mediated factors such as interleukin-31, leukotriene B4 and Substance P have also been implicated in pruritoceptive itch. Ultimately, the diversity of these findings is a testament to the complexity and multifactorial biological origins of itch.

The role of serotonin

Serotonin is a neurotransmitter, which refers to a chemical produced by the body that enables brain cells and other nervous system cells to communicate with one another.

Serotonin is another potent inducer of itch, whose role is becoming increasingly elucidated. In humans, abnormal serotonin signaling has been linked to itch in atopic dermatitis (commonly known as eczema), as well as other disorders such as allergy, renal failure, hepatobiliary disorders, and psoriasis. In a study led by Zhou-Feng Chen PhD and colleagues at the Washington University School of Medicine Center for the Study of Itch, serotonin was first implicated in itch. As part of the study, Dr. Chen’s research team genetically engineered a strain of mice that lacked the ability to make serotonin. When these mice were injected with a substance that normally produces itch in the skin, they demonstrated a reduced degree of scratching compared to their genetically normal littermates. After injection with serotonin, however, the genetically engineered mice scratched at a frequency that would be expected in response to the itchy stimuli.

Ultimately, the researchers demonstrated that a lack of serotonin expression corresponded to a reduced proclivity in mice for scratching. Although fascinating, the potential translation of this finding to clinical treatment would be unfortunately limited – serotonin is involved in various processes in the body, including aging, growth, bone metabolism, circadian rhythm, and mood regulation. Thus broad, non-specific serotonin blockade would have consequences on a number of physiological processes.

But further experiments were performed to investigate the communication between serotonin and spinal nerve cells that specifically transmit itch. Dr. Chen’s research team successfully isolated the receptor used by serotonin to activate the itch-specific neurons, 5HT1A. Moreover, they blocked this specific receptor and found again that mice scratched with reduced frequency.

In this most recent study conducted by Drs. Bautisa and Brem’s research teams, researchers examined the available scientific literature to identify genes whose expression correlated with itch behavior in experimental strains of mice. In doing so, the serotonin receptor HTR7 was isolated as a potential molecular candidate to study: mice that expressed the highest degree of HTR7 in nerve cells in the skin were also the ones most affected by itch.

A panel of follow-up experiments were performed that demonstrated how activation of HTR7 led to molecular signaling through TRPA1 (a member of the TRP family of ion channels that have been well-characterized in triggering itch). In a subsequent experiment examining a mouse model of atopic dermatitis, mice that lacked HTR7 or TRPA1 both displayed reduced scratching behaviors. In fact, their skin lesion severity was also reduced compared to equivalent mice with intact HTR7 and TRPA1 genes.

Future directions:

It is promising that altered serotonin signaling has been identified in a variety of dermatologic disorders such as allergy-induced itch as well as psoriasis. More broadly, chronic itch is associated with systemic disorders as well — for example, kidney failure, cirrhosis and cancer — and can be equally as debilitating as it is for atopic dermatitis patients. It is of great interest that we expand our understanding of itch, as a common symptom for which effective treatments are limited, leading to frustration and suffering for affected patients. Thus the identification of HRT7 as a player in chronic itch, as led by the research teams of Dr. Bautista and Dr. Brem, is a major breakthrough in this field. Both HTR7 and the future directions now open for further research offer hope for the development of novel drug targets to treat chronic itch. For patients, this will ideally set the stage for greater symptom control and improved quality of life for patients who suffer from eczema and other conditions.

Sources

Garibyan L, Rheingold CG, Lerner EA. Understanding the pathophysiology of itch. Dermatol Ther. 2013 Mar-Apr; 26(2):84-91.

Morita T, McClain SP, Batia LM, et al. HTR7 mediates serotonergic acute and chronic itch. Neuron. 2015 Jul 1; 87(1): 124-38. Doi:10.1016/j.neuron.2015.05.044. Epub 2015 Jun 11.

Potenzieri C, Undem BJ. Basic mechanisms of itch. Clin Exp Allergy. 2012 Jan; 42(1):8-19.

Zhao ZQ, Liu XY, Jeffry J, et al. Descending control of itch transmission by the serotonergic system via 5-HT1A-facilitated GRP-GRPR signaling. Neuron. 2014 Nov 19;84(4):821-34.

Monica Enamandram 1Monica Enamandram, MD is a resident physician in the Department of Dermatology at Stanford University Hospitals. She is a graduate of Harvard Medical School, and is interested in patient education, advocacy, and clinical research in dermatology. Monica is excited to develop successful preventive measures and improved treatment regimens for eczema.