Cutaneous allergic contact dermatitis responses are diminished in mice deficient in neurokinin 1 receptors and augmented by neurokinin 2 receptor blockage

ABSTRACT Sensory neuropeptides such as neurokinin A (NKA) or particularly substance P (SP) by neurokinin receptor (NK‐R) activation modulate skin and immune cells functions during neurogenic inflammation. In this study, we examined the relative importance of SP/NK‐1Rs or NKA/NK‐2Rs in a murine model for allergic contact dermatitis (ACD) and tested if the functional absence of NK‐Rs will impair inflammatory response in vivo. Mice lacking NK‐1Rs (C57BL/6J‐NK‐1R•/•) displayed a significantly reduced ACD inflammatory ear swelling response to dinitrofluorobenzene (DNFB) with histological less edema and 50% fewer infiltrating leukocytes compared with the ACD response in wild‐type (+/+) animals. In NK‐1R+/+ mice, transient NK‐1R inhibition impaired ACD sensitization. In vitro haptenized bone marrow‐derived dendritic cells from NK‐1R+/+ mice matured in the presence of an NK‐1R antagonist displayed a reduced capability to induce T cell proliferation in vitro and ACD after adoptive transfer into naïve wild‐type mice in vivo. By contrast, NK‐2R inhibition significantly enhanced the ACD response in NK‐1R null or in wild‐type mice, whereas epicutaneous application of NK‐2R agonists diminished the ACD inflammation. Thus, NK‐1R and SP are required for antigen sensitization and a full inflammatory response to cutaneous allergens and NKA and the NK‐2R mediate a contrasting anti‐inflammatory role in ACD. Thus, SP, NKA, NK‐1R, and NK‐2R have important but differential roles in the regulation of cutaneous inflammatory responses.