Associate Professor of Dermatology Harvard Medical School

Physician Investigator (NonCl) Cutaneous Biology Research Center, Mass General Research Institute

insect hormones; insect proteins; itch; mechanisms of itch; melanophores; mrgprx2; mucunain; par2; protease-activated receptor 2; pruritus; receptors pituitary adenylate cyclase-activating polypeptide; receptors proteinase-activated; scabies; spinal ganglia; type i; vasodilator agents Itch is an unpleasant sensory experience leading to the desire to scratch. Itch can be so severe as to be disabling. It is a widespread symptom of both skin disease and systemic disease as manifest in the skin. Common conditions in which the sensation of itch is initiated in the periphery include atopic dermatitis or eczema, psoriasis, contact dermatitis, fungal infections such as athlete’s foot and parasitic infestations such as scabies. Kidney failure and certain liver conditions are often associated with severe itching. Itch can occur in lung cancer and may be an early symptom of Hodgkin’s lymphoma. More than 50% of people over 70 years of age have itching without a known cause but it is not simply from having dry skin.

Itch is the most common symptom encountered by dermatologists and one of the most challenging problems to treat. Itch is difficult to treat because it is poorly understood and drugs, such as antihistamines, do not usually target the underlying cause.

Our approach to itch started with our identification of the active component of itching powder. Itching powder consists of little hairs, or spicules, that cover the pods of a plant, Mucuna pruriens, also known as cowhage. The active component is called mucunain, We determined that mucunain is a type of protein called a protease, or enzyme. Proteases cut other proteins. Mucunain contains the amino acid cysteine at its active site and is thus considered a cysteine protease. Several other cysteine proteases from plants also cause itching. These include bromelain from pineapples, ficin from figs, and papain from papaya. Papain is the enzyme in meat tenderizer.

We asked if there were a human enzyme similar to mucunain. We determined that there was, by using data from sequencing of the human genome. The human enzyme is called cathepsin S. When put into the skin, cathepsin S causes itching, just like itching powder.

We next sought to determine how cathepsin S and mucunain cause itch. We suspected that these enzymes were likely to turn on a molecule called a receptor present on skin cells called keratinocytes and on nerves in the skin. We found that cathepsin S and mucunain turned on a receptor called protease-activated receptor 2 or PAR2. We next found that they also turn on a receptor called MRGPRX2, implicating this very important receptor in itch for the first time. We have found that another molecule, substance P, also induces itch via MRGPRX2. Turning on these receptors results in a signal being sent from the skin to the brain that leads to the sensation of itch, as shown in the animation.

We are optimistic that blocking these receptors will lead to new therapies, not only for itch, but also inflammation.