During a PRF webinar on October 1, 2019, Brian Kim discussed neuroimmune mechanisms of chronic itch. After his talk, there was a Q&A period moderated by Sarah Ross.
- Brian Kim, MD, Washington University School of Medicine, St. Louis, US
- Sarah Ross, PhD, University of Pittsburgh, US
Listen to the webinar
Here is an abstract of Kim’s talk:
The type 2 immune response has evolved to arm the mammalian host with the capacity to expel macroparasites, toxins, and environmental irritants from barrier surfaces. One critical aspect of this defense mechanism is stimulating the protective behavioral response of scratching. The key neuroimmune interactions that promote this response remain poorly understood, particularly in the setting of pathologic chronic itch. We have recently discovered two novel mechanisms that drive the development of chronic inflammatory itch in the skin. While mast cells are well-known mediators of acute histamine-mediated (histaminergic) itch, how they drive chronic itch is not well understood. Classically, mast cell activation and histamine release are mediated by IgE cross-linking at the cell surface. However, we have identified a novel IgE-independent mechanism by which mast cells are activated via the GPCR Mrgprb2 to mediate nonhistaminergic itch. Additionally, we have uncovered previously unrecognized roles for the hallmark type 2 effector cytokines, IL-4 and IL-13. These cytokines can directly stimulate itch sensory neurons to promote itch. Indeed, neuron-specific deletion of IL-4Rα or downstream JAK1 critically abated the development of chronic itch in vivo. In contrast to the itch-inducing cytokine IL-31, canonical type 2 cytokines mediate itch by promoting neuronal hypersensitivity to a variety of pruritogens including IL-31 and histamine. Thus, antagonizing the neuronal IL-4Rα-JAK1 axis likely represents a unique antipruritic therapeutic strategy. Collectively, these findings provoke the hypothesis that type 2 immune responses may have evolved to alter behavior and promote mechanical reflexes (e.g., scratching) for the expulsion of specific pathogens such as helminths. Importantly, our findings highlight novel neuroimmune interactions that may lead to innovative targets for the treatment of a diverse array of inflammatory skin disorders.
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See previous PRF webinars here.