Abstract
Cutaneous neurogenic inflammation is a complex biological response of the host immune system to noxious stimuli. Present evidence suggests that zinc metalloproteases may play an important role in the regulation of neurogenic inflammation by controlling the local availability of neuropeptides, such as substance P (SP), that are capable of initiating or amplifying cutaneous inflammation after release from sensory nerves. To address the hypothesis that the dipeptidyl carboxypeptidase angiotensin-converting enzyme (ACE) is capable of modulating skin inflammation, we have analyzed murine allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD) using wild-type C57BL/6J (ACE(+/+)) or genetically engineered mice with a heterozygous deletion of somatic ACE (ACE(+/-)). In 2,4-dinitro-1-fluorobenzene-sensitized ACE(+/-) mice, ACD was significantly augmented in comparison to ACE(+/+) controls as determined by the degree of ear swelling after exposure to hapten. Likewise, systemic treatment of ACE(+/+) mice with the ACE inhibitor captopril before sensitization or elicitation of ACD significantly augmented the ACD response. In contrast, local damage and neuropeptide depletion of sensory nerves following capsaicin, injection of a bradykinin B(2), or a SP receptor antagonist before sensitization significantly inhibited the augmented effector phase of ACD in mice with functionally absent ACE. However, in contrast to ACD, the response to the irritant croton oil was not significantly altered in ACE(+/-) compared with ACE(+/+) mice. Thus, ACE by degrading bradykinin and SP significantly controls cutaneous inflammatory responses to allergens but not to irritants, which may explain the frequently observed exacerbation of inflammatory skin disease in patients under medication with ACE inhibitors.
Highlights
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The role of NEP in modulating neuropeptide-mediated biological responses and systemic inflammation is supported by a number of recent in vivo studies demonstrating that NEPϪ/Ϫ animals are highly sensitive to bacterial endotoxins [29] and the absence of NEP promotes intestinal [30] as well as cutaneous inflammatory response to allergens [24]
angiotensinconverting enzyme (ACE) inhibition enhanced short-term (Ͻ24 h) skin inflammation induced by OVA, capsaicin, or BK injection the extent of inflammation was dependent on the ACE inhibitor used [34, 35]
Summary
NEP, neutral endopeptidase; ACD, allergic contact dermatitis; ACE, angiotensin-converting enzyme; Ang, angiotensin; BK, bradykinin; B-R, BK receptor; B2-R, BK 2 receptor; DC, dendritic cell; DNFB, 2,4-dinitro-1fluorobenzene; ICD, irritant contact dermatitis; NK-1R, neurokinin 1 receptor; SP, substance P. In the ACEϪ/Ϫ animals, the lack of ACE resulted in a dramatic reduction of the blood pressure, indicating the absence of a mechanism that is capable of compensating for the loss of ACE. Our results indicate that the acute or permanent inhibition of ACE results in an increased cutaneous inflammatory response to allergens but not to irritants. These results implicate the BK- and SP-proteolytic enzyme ACE as an important modulator of ACD inflammatory responses in the skin
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