Immune Regulation of Atopic Itch

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PROJECT SUMMARY/ABSTRACT Atopic dermatitis (AD) is a chronic, relapsing skin disease that affects children and adults. This disease is a growing public health problem and a large economic burden worldwide. The central and most debilitating symptom in AD is chronic itch. While some patients can be treated successfully with existing therapies, there is a continuing need for the development of new therapies to treat patients who do not respond to current AD treatment strategies. We and others have shown that the production of the type 2 cytokines interleukin (IL)-4 and IL-13 by T helper type 2 (TH2) cells and newly identified group 2 innate lymphoid cells (ILC2s) contribute to AD pathogenesis. Preliminary studies have also shown that the receptors for IL-4 and IL- 13 are highly expressed on itch-sensing primary sensory neurons. However, the precise role of TH2 cells, ILC2s and type 2 cytokines in mediating AD-associated itch remains poorly defined. Further, type 2 cytokines are known to be dependent on Janus kinase (JAK) signaling in immune cells for their effector functions. However, whether JAK signaling in primary sensory neurons elicits itch remains unknown. The central hypothesis of this proposal is that atopic itch arises from interactions between type 2 immune cells and primary sensory neurons via JAK signaling. To test this, in Specific Aim 1 we will employ genetically modified TH2 cell- and/or ILC2-deficient mice to investigate the role of these immune cells and their associated cytokines in evoking neuronal excitation and itch behavior. In Specific Aim 2, we will employ Cre-dependent conditional knockout mice in which Jak1 is selectively deleted from immune cells or primary sensory neurons to determine whether sensory neuron-specific JAK signaling mediates pruritogen-elicited neuronal activation and itch responses. We anticipate that gaining a better understanding of the immunologic pathways that interact with the primary pruriceptors to promote itch in the context of AD could lead to new anti-itch therapies.