Neutral endopeptidase terminates substance P-induced inflammation in allergic contact dermatitis

Sensory nerve-derived neuropeptides such as substance P demonstrate a numbe r of proinflammatory bioactivities, but less is known about their role in i nflammatory skin disease. The cell surface metalloprotease neutral endopept idase (NEP) is the principal proteolytic substance P-degrading enzyme. This study tests the hypothesis that the absence of NEP results in dysregulated inflammatory skin responses. The effector phase of allergic contact dermat itis (ACD) responses was examined in NEP-/- knockout and NEP+/+ wild-type m ice and compared with the irritant contact dermatitis response in these ani mals. NEP was found to be normally immunolocalized in epidermal keratinocyt es and dermal blood vessels. The ACD ear swelling response was 2.5-fold hig her in animals lacking NEP and was accompanied by a significant increase in plasma extravasation and infiltration of inflammatory leukocytes. The augm ented ACD response in NEP-/- animals was abrogated by either administration of a neurokinin receptor 1 antagonist or by repeated pretreatment with top ical capsaicin. Similar to NEP-/- mice, the acute inhibition of NEP in NEP/+ animals resulted in an augmented ACD response. In contrast to the ACD re sponses, little differences were observed in the irritant contact dermatiti s response of NEP-/- compared with NEP+/+ animals after epicutaneous applic ation of the skin irritants croton oil or SDS. Thus, these results indicate that NEP and cutaneous neuropeptides have a significant role in the pathog enesis of ACD.