Chronic itch is debilitating symptom that severely limits quality of life and affects up to 20% of the population. Despite this, there are no FDA-approved drugs specifically indicated for the treatment of itch. Our current understanding of chronic itch pathophysiology largely derives from studying inflammatory disorders such as atopic dermatitis (i.e. eczema). Thus, how chronic itch arises in conditions that lack overt cutaneous inflammation is poorly understood. A notable example is chronic pruritius of unknown origin (CPUO), which accounts for 10- 40% of all chronic itch cases and lacks effective treatments. Improper barrier function due to dry, aging skin may be a key driving factor of chronic itch in CPUO, yet what may mediate this is unknown. IL-33 is an ?alarmin? released from keratinocytes upon damage or stress. Our preliminary data suggests that IL- 33 is elevated in the serum of CPUO patients compared to healthy controls. Furthermore, a recent study has shown that IL-33 is required for the development of dry skin itch in a murine model that recapitulates several of key aspects of CPUO. However, the precise mechanisms by which IL-33 promotes itch and how this promotion is regulated remain largely unexplored. IL-33 is a key inducer of immune cell responses, however, we and others have found that IL-33 can directly activate sensory neurons. Thus, in Aim 1, I will determine if IL-33 is a key mediator of a direct epithelial-neuronal axis in dry skin itch using novel mice I have generated. The activity of IL- 33 is dramatically enhanced upon extracellular cleavage by proteases. Our preliminary data suggest that KLK7, a serine protease that is important for barrier homeostasis, promotes chronic itch through an unknown, indirect mechanism.
In Aim 2, I will evaluate if KLK7 cleaves IL-33, and enhances IL-33?s bioactivity and capacity to induce itch. Together, this work aims to address a unmet need in medicine by shedding light on novel mechanisms underlying the poorly understood condition of CPUO.
Chronic itch is a prevalent, debilitating symptom that is difficult to treat due to a poor understanding of its pathophysiology. The goal of this proposal is to determine key mechanisms by which skin barrier disruption drives chronic itch, and ultimately shed light on novel therapeutic targets for this highly unmet need in medicine.
