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

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Abstract
SPECIFIC AIMS Sensory nerves respond to noxious stimuli by releasing neuropeptides such as the tachykinins substance P (SP) and neurokinin A (NKA). In previous studies, a primary role for SP and its principal neurokinin 1 receptor (NK-1R) was suggested for the initiation and propagation of neurogenic inflammation as part of the inflammatory process in general and also as a component of certain skin disorders such as psoriasis or allergic contact dermatitis (ACD), but the exact role of NKA and the NK-2R in these events is less determined. The availability of mice lacking the NK-1R (NK-1R−/−) allowed us to explore whether alterations in the SP/NK-1R system may dysregulate inflammatory skin responses and to determine the relative contribution of SP and NKA and their respective receptors, NK-1R and NK-2R, on the outcome of an inflammatory response in the skin. PRINCIPAL FINDINGS 1. Diminished allergic contact dermatitis (ACD) responses in NK-1R−/− mice and modulation of ACD sensitization by blocking of NK-1R In a murine model for ACD as a model for T cell-mediated skin inflammation, inflammatory responses were significantly diminished in NK-1R-deficient mice sensitized to the antigen dinitrofluorobenzene (DNFB) compared with NK-1R+/+ animals, as determined by measurement of ear swelling, which resulted from challenge of the animals with the same antigen on one ear after 5 days to elicit the efferent phase of ACD (Fig. 1 ⤻ a). Histologically, NK-1R−/− mice had less dermal edema and epidermal hyperplasia and displayed fewer infiltrating leukocytes in the affected skin area (51.3±18.6% vs. NK-1R+/+, P+/+ mice, transient systemic administration of an NK-1R antagonist (NK-1RA) before ACD antigen sensitization significantly diminished the ACD inflammatory response after antigen challenge (Fig. 1b⤻ ). We hypothesized that this transient NK-1R inhibition may functionally impair APC such as epidermal Langerhans cells and dermal dendritic cells (DC), which are fundamentally important for ACD sensitization. Bone marrow-derived dendritic cells (BMDC) generated from wild-type (wt) mice matured with GM-CSF/IL-4 in the presence of a NK-1RA for 7 days expressed fewer DC maturation markers and costimulatory molecules than did BMDC not exposed to the antagonist (data not shown). Adoptive transfer of BMDC in vitro haptenized with the soluble DNFB analog dinitrobenzene sulfonic acid (DNBS) into naive wt mice profoundly increased ACD ear swelling after DNFB challenge compared with mice injected with unpulsed BMDC (Fig. 1b⤻ ). Mice injected with NK-1RA-treated, haptenized BMDC demonstrated a markedly reduced ACD inflammatory response after antigen challenge compared with recipient mice injected with haptenized BMDC not treated with the antagonist (Fig. 1b⤻ ). In addition, the presence of a NK-1RA significantly reduced the mixed lymphocyte reaction between hapten-specific proliferation of T cells isolated from DNFB-sensitized NK-1R+/+ mice exposed to Ag-laden BMDC (data not shown). Thus, the presence of NK-1R and activation by SP is mandatory for ACD sensitization, interaction of DC and T cells, and a full inflammatory response to cutaneous allergens. Figure 1. Diminished ACD response in NK-1R−/− mice and modulation of ACD sensitization by blocking of NK-1Rs. NK-1R−/−, and NK-1R+/+ mice were sensitized with 0.5% DNFB on the shaved abdomen and challenged with 0.2% DNFB on the right ear on day 5 (a). The ACD response was determined by the degree of ear swelling of the hapten-exposed ear compared with that of the vehicle-treated contralateral ear before and after DNFB challenge (s+c). Some mice were challenged only with DNFB without prior sensitization (c only). b) NK-1R+/+ mice were sensitized and challenged as above (positive control; s+c). 1 × 106 DNBS-haptenized BMDC generated from NK-1R+/+ mice were matured in the presence or absence of a NK-1RA ( SR140333 1 μM) and injected i.v. into the tail vein of naive wt mice [“+DC (D)” or “+DC (N, D)”]. Some mice were injected with untreated or NK-1RA-treated BMDC that were not haptenized with DNBS [“DC (control)”] or [“DC (N)”]. Some mice were treated with 1 μmol/kg SR140333 30 min before sensitization [“N, s+c”]. All mice were challenged (“c”) after 5 days and ear swelling was determined as above. Ear swelling values in μm as mean ± se, n = 5–8. a) ***P < 0.001 for NK-1R−/− vs. NK-1R+/+ mice. b) **P < 0.01 for “DC (N, D)” vs. “DC (D)”; #P < 0.05 and ##P < 0.01 for “DC (N, D)” and “N, s + c” vs. PoCo “s + c”; +++P < 0.001 for “DC (D), c” and “DC (D, N), C” vs. “DC (control), c” and “DC (N), c.” Download figure Download PowerPoint 2. Modulation of ACD responses in NK-1R+/+ and NK-1R−/− mice by agonists and antagonist of the NK-2R We next examined the relative contribution of NKA and NK-2R in the murine ACD response. Local epicutaneous or systemic application of a potent and highly specific NK-2R antagonist (GR 94800) during the first 6 h of the efferent phase of ACD significantly augmented ACD inflammatory responses in NK-1R+/+ mice (Fig. 2 ⤻ a) and in animals lacking NK-1Rs (Fig. 2b⤻ ). By contrast, epicutaneous NK-2R agonists such NKA or βAla8NKA(4-10) after hapten challenge significantly diminished ACD inflammatory responses (Fig. 2a⤻ ). Immunohistochemical examination...
Funding Information
  • Deutsche Forschungsgemeinschaft (SFB293, 87/E1)
  • Deutsche Forschungsgemeinschaft (Scho 629/1‐1, Scho 629/3‐1)