Neuropeptides, a never‐ending story? Termination of cutaneous inflammation by proteolytic peptidases

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Neuropeptide‐specific peptidases such as neutral endopeptidase (NEP, CD10) and angiotensin‐converting enzyme (ACE, CD143) effectively control the bioavailability of neuropeptides released from sensory nerves, immune and skin cells during neurogenic inflammation. Drug inhibition or genomic deletion of NEP or ACE results in a substance P (SP‐) and bradykinin‐dependent augmentation of murine allergic contact dermatitis (ACD) by affecting ACD sensitization and elicitation. The functional absence of NEP enhanced ACD inflammation by promoting bone marrow‐derived dendritic cell (BmDC) maturation and function. In vitro haptenized BmDCs from NEP–/– mice neurokinin‐1 receptor‐dependently stimulated proliferation of antigen‐specific NEP–/– and NEP+/+ T cells with higher efficacy compared to NEP+/+‐mice BmDCs. Importantly, adoptive transfer of in vitro haptenized DC from NEP–/– into wild‐type mice significantly promoted ACD in comparison with transfer of NEP+/+DC. Likewise, hapten uptake into DC from regional lymph nodes during ACD sensitization is increased in NEP–/– mice compared to normal mice. Moreover, in CD10‐ and CD143‐expressing human dermal microvascular endothelial cells and keratinocytes, UV light and inflammatory mediators regulated mRNA and protein expression, as well as proteolytic activity of these peptidases, which may be important for cell survival and the outcome of an inflammatory response. Likewise, NEP and ACE are also involved in the proteolytic processing of neuroendocrine hormones such as adrenocorticotropin and α‐melanocyte‐stimulating hormone. Thus, present data indicate that ACE and NEP by proteolytic cleavage of peptide mediators have a significant role in controlling cutaneous inflammatory responses.