Abstract
The bioavailability of neuropeptides such as substance P (SP) released from sensory nerves or immune cells during skin inflammation is effectively controlled by proteolytic peptidases. Acute inhibition or genomic deletion of neutral endopeptidase (NEP) results in a SP‐dependent augmentation of murine allergic contact dermatitis (ACD) by affecting sensitization and elicitation phase. In this study, we address the hypothesis that absence of NEP may modulate ACD responses by affecting bone marrow‐derived dendritic cell (BmDC) maturation and function. BmDCs were generated from NEP‐deficient mice (C57BL/6J‐NEP–/–) or wild‐type controls (C57BL/6J). FACS analysis revealed that d3, d6 and d7 NEP–/– BmDCs expressed significantly more DC cell‐surface markers and costimulatory molecules compared to NEP+/+ mice BmDCs, in particular after BmDC maturation with LPS. In MLR utilizing d8 BmDCs pulsed 3 h in vitro with DNBS and T cells from in vivo DNFB‐haptenized NEP–/– and NEP+/+ mice, BmDCs from NEP–/– animals promoted proliferation of T cells with higher efficacy compared to wild‐type mice BmDCs. Likewise, T cells from NEP–/– mice demonstrated a higher proliferative response to Concavalin A stimulation or CD3/CD28 ligation compared to NEP+/+ mice. In addition, acute systemic NEP inhibition in NEP+/+ mice prior to sensitization with fluorescein isothiocyanate (FITC) after 24 h significantly augmented uptake of FITC in the CD11c‐positive DC fraction from regional lymph nodes but not from spleen compared to cells obtained from mice not treated with the NEP inhibitor. These data indicate that functional absence of NEP may significantly control cutaneous ACD inflammatory responses by promoting hapten uptake, DC maturation and T‐cell stimulation.
Published Version
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