Date of Award
Doctor of Philosophy (PhD)
Chronic itch, defined as symptoms of itch lasting longer than six weeks, is a highly debilitating symptom of many medical conditions. Further, in some inflammatory skin disorders such as atopic dermatitis (AD), chronic itch is a key diagnostic criterion. Notably, unlike the well-described mediators of acute itch, the critical factors that promote chronic itch in specific disease contexts are widely unknown. As a result, therapeutic options for chronic itch are limited. In AD, the type 2 cytokines interleukin (IL)-4 and IL-13 are known to drive skin inflammation. Dupilumab, a recently developed monoclonal antibody that reduces both IL-4 and IL-13 signaling by targeting their shared receptor subunit IL-4 receptor alpha (IL-4R_), has demonstrated remarkable efficacy in treating AD, including unprecedented improvements in chronic itch. However, despite our understanding of the role of type 2 cytokines in AD pathogenesis, it remains unclear whether these proinflammatory mediators can also directly affect the sensory nervous system to shape sensations of itch. Further, whether associated downstream neuronal signaling pathways can be exploited therapeutically remains unexplored. We have found that type 2 cytokines directly stimulate sensory neurons in both mice and humans and activate neurons along recently described itch pathways. Employing AD as a model chronic itch disorder, we observed that sensory neuron-specific expression of IL-4R_ is necessary for chronic itch through its ability to modulate responses to multiple known pruritogens. Thus, beyond their known proinflammatory roles, we have identified a previously unrecognized function of type 2 cytokines in the sensory nervous system. Based on known IL-4R_ signaling biology in immune cells, we hypothesized that downstream Janus kinase 1 (JAK1) signaling in neurons would also be a critical component of itch. Indeed, neuron-specific deletion of JAK1 resulted in abatement of itch in mice. Further, in translational studies, JAK inhibition in patients with recalcitrant chronic itch, including those patients with AD-associated itch, idiopathic itch, as well as itch associated with germline JAK1 gain-of-function mutations, has resulted in marked improvements of itch symptoms. Collectively, these studies demonstrate that neuronal type 2 cytokine and JAK1 signaling pathways represent a new paradigm of neuroimmunologic interactions and may serve as novel therapeutic targets for AD and other chronic itch disorders.
Chair and Committee
Brian S. Kim
Marco Colonna, Michael J. Holtzman, Chyi-Song Hsieh, Hongzhen Hu,
Oetjen, Landon Kyle, "Neuroimmunologic Regulation of Chronic Itch" (2020). Arts & Sciences Electronic Theses and Dissertations. 2227.
Available for download on Wednesday, May 15, 2120