ABSTRACT Allergic contact dermatitis (ACD) is a highly common chronic inflammatory skin disease initiated by skin exposure to a hapten, which triggers local neuroinflammatory responses and promotes the activation of pathogenic Type 1 biased effector T cells that sustain the chronicity of the disease. There is an unmet need for specific immunotherapies to treat ACD, and development of these treatments requires a thorough understanding of the cellular and molecular mechanisms of the disease. During hapten penetration of the skin, signaling the neurokinin-1 receptor (NK1R) by the proinflammatory neuropeptides substance P and hemokinin-1 promotes cutaneous inflammation. This proinflammatory skin environment is required for the T cell-stimulatory and Type 1 biasing function of resident dendritic cells (DCs). Because lacking NK1R in mice impairs the development of ACD it has been proposed that blockade of the receptor could be beneficial to treat the disease. Understanding the impact of NK1R-signaling in the immune response to haptens is of fundamental relevance for therapies attempting to inhibit the function of the receptor to treat ACD. Nonetheless, the cellular and molecular mechanisms and the pathogenic consequences of hapten- mediated NK1R activation in the skin remain to be elucidated. Keratinocytes constitute the first line of defense affected by contact sensitizers and they have per se a relevant role in innate and adaptive components of skin-initiated immune responses. Keratinocytes are the main cell subset that expresses constitutively the NK1R. Using NK1Rfl/fl mice, we published that specific deletion of the NK1R in keratinocytes impairs the synthesis and secretion of IL-1β, a cytokine necessary for the activation of T-cell stimulatory DCs, and inhibits the innate and adaptive immune responses of ACD. Therefore, we hypothesize that: “Keratinocytes are early cell targets of hapten-mediated NK1R-signaling, and that they are required to generate the proinflammatory skin environment that supports the innate and effector immune responses of ACD”. We will address this hypothesis in the following specific aims. Specific aim 1 will analyze the mechanisms of the proinflammatory effects caused by NK1R-signaling in keratinocytes exposed to haptens. Specific aim 2 will analyze the mechanisms of intercellular communication by which keratinocytes interact with skin resident DCs to promote their T cell stimulatory functions during hapten initiated skin inflammation. Specific aim 3 will analyze the role of the NK1R-signaling exclusively in keratinocytes in the generation of the effector and memory T cells of ACD. Our studies include in vitro and in-vivo mouse models and ex-vivo human skin models to test the translational relevance of our experiments. If successful, the data generated through this application will provide highly relevant missing information for the development of efficient specific therapies for the prevention and treatment of ACD.