Neutral endopeptidase and angiotensin‐converting enzyme – key enzymes terminating the action of neuroendocrine mediators

Abstract

Zinc-metalloproteases, such as neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), effectively control the bioavailability of peptide mediators released from sensory nerves, immune and skin cells during the cutaneous response to endogenous or exogenous noxious stimuli. Functional inactivation of NEP or ACE by transient inhibition or permanent genomic deletion results in a relative abundance of substance P (SP) and bradykinin (BK); this augments murine allergic contact dermatitis (ACD) by affecting ACD sensitization and elicitation, which involves neurokinin 1 receptors (NK1), BK receptors (B2) and an intact cutaneous sensory nervous system. Present evidence suggests that increased SP via NK(1) is capable of boosting important functions of SP- and NK1-expressing dendritic cells (DCs) and T cells (TCs) in an auto- or paracrine manner, which promotes ACD antigen sensitization. Moreover, skin inflammation or wounding in vivo, as well as treatment of epidermal and dermal cells by UV light and inflammatory mediators in vitro, regulates NEP and ACE expression and activity. Likewise, NEP and ACE are capable of processing neuroendocrine hormones, such as adrenocorticotropin and alpha-melanocyte-stimulating hormone. Thus, present data indicate that ACE and NEP, via proteolytic cleavage of peptide mediators and growth factors, represent important control factors for the inflammatory response in skin disorders such as psoriasis or allergic inflammation, but may also be capable of affecting pigmentation, cell survival, wound healing and tissue regeneration.