Cutaneous allergic contact dermatitis responses are diminished in mice deficient in neurokinin 1 receptors and augmented by neurokinin 2 receptor blockage.
Sensory neuropeptides such as neurokinin A (NKA) or particularly substance P (SP) by neurokinin receptor (NK-R) activation modulate skin and immune cells functions during neurogenic inflammation. In this study, we examined the relative importance of SP/NK-1Rs or NKA/NK-2Rs in a murine model for allergic contact dermatitis (ACD) and tested if the functional absence of NK-Rs will impair inflammatory response in vivo. Mice lacking NK-1Rs (C57BL/6J-NK-1R-/-) displayed a significantly reduced ACD inflammatory ear swelling response to dinitrofluorobenzene (DNFB) with histological less edema and 50% fewer infiltrating leukocytes compared with the ACD response in wild-type (+/+) animals. In NK-1R+/+ mice, transient NK-1R inhibition impaired ACD sensitization. In vitro haptenized bone marrow-derived dendritic cells from NK-1R+/+ mice matured in the presence of an NK-1R antagonist displayed a reduced capability to induce T cell proliferation in vitro and ACD after adoptive transfer into naïve wild-type mice in vivo. By contrast, NK-2R inhibition significantly enhanced the ACD response in NK-1R null or in wild-type mice, whereas epicutaneous application of NK-2R agonists diminished the ACD inflammation. In conclusion, NK-1R and SP are required for antigen sensitization and a full inflammatory response to cutaneous allergens and NKA and the NK-2R mediate a contrasting anti-inflammatory role in ACD. Thus, SP, NKA, NK-1R, and NK-2R have important but differential roles in the regulation of cutaneous inflammatory responses.
Scholzen
Thomas E
TE
Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, Department of Dermatology, University of Münster, Von-Esmarch-Strasse 58, 48149 Münster, Germany. thoscho@uni-muenster.de
Steinhoff
Martin
M
Sindrilaru
Anca
A
Schwarz
Agatha
A
Bunnett
Nigel W
NW
Luger
Thomas A
TA
Armstrong
Cheryl A
CA
Ansel
John C
JC
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D017449:Dermatitis, Allergic Contact / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D017353:Gene Deletion; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology
D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2