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. In conclusion, 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.

Substance P Is a Key Mediator of Stress-Induced Protection from Allergic Sensitization via Modified Antigen Presentation

“…In these experiments, SP activation of DC during the effector phase of a Th1-driven inflammation triggered a massive and rapid LC mobilization out of the epidermis and enhanced inflammation. An inflammation-promoting effect of SP signaling was also demonstrated in other Th1 and neurogenic inflammation-dominated neuroimmune constellations, such as during the elicitation of contact hypersensitivity (7,58,59), during provocation of AlD (32)(33)(34), in hair loss (60), and in healthy murine skin and lymphocytes (34,39,40). This effect appears to be further facilitated by stress-and nerve growth factor-induced plasticity of the peripheral nervous system and malfunctioning HPA responsiveness (32,34,39,61,62).…”

Kinetics of neuronal contribution during the development of a contact allergic reaction

“…Kinkelin et al [12] found no diVerence in the expression of dermal PGP 9.5-ir nerve Wbres in the contact eczematous skin compared to control skin. However, the expression of epidermal PGP Several reports have been published on the involvement of sensory neuropeptides in ACD [7,18,23]. Thus, the implication of these messengers in established ACD is evident and has earlier been documented.…”

“…Substance P and neurokinin A (NKA) are members of the tachykinin family that are known to be implicated in murine ACD [18]. Substance P and NKA have an agonizing eVect on preferentially neurokinin-1 (NK-1) receptor (R) and NK-2R, respectively [14,15].…”

In Vivo Signaling through the Neurokinin 1 Receptor Favors Transgene Expression by Langerhans Cells and Promotes the Generation of Th1- and Tc1-Biased Immune Responses

“…In the skin, signaling through the NK1R with SP or NK1R agonists prevents cutaneous tolerance induced by UV-B light and favors delayed-type hypersensitivity (DTH) reactions through the release of IL-12p70, a potent Th1-biasing cytokine (19,23). Taken together, these observations highly suggest that signaling via the NK1R during the initiation of skin-mediated immune responses will favor development of Th1 effector immunity.…”