Skin codelivery of contact sensitizers and neurokinin-1 receptor antagonists integrated in microneedle arrays suppresses allergic contact dermatitis.
Contact dermatitis
contact hypersensitivity
hapten
immunosuppressive therapies
keratinocytes
microneedle arrays
neurokinin-1 receptor
neurokinin-1 receptor antagonists
neuropeptides
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
received:
12
06
2021
revised:
03
11
2021
accepted:
03
12
2021
pubmed:
28
1
2022
medline:
14
7
2022
entrez:
27
1
2022
Statut:
ppublish
Résumé
Allergic contact dermatitis (CD) is a chronic inflammatory skin disease caused by type 1 biased adaptive immunity for which there is an unmet need for antigen (Ag)-specific immunotherapies. Exposure to skin sensitizers stimulates secretion of the proinflammatory neuropeptides substance P and hemokinin 1, which signal via the neurokinin-1 receptor (NK1R) to promote the innate and adaptive immune responses of CD. Accordingly, mice lacking the NK1R develop impaired CD. Nonetheless, the role and therapeutic opportunities of targeting the NK1R in CD remain to be elucidated. We sought to develop an Ag-specific immunosuppressive approach to treat CD by skin codelivery of hapten and NK1R antagonists integrated in dissolvable microneedle arrays (MNA). In vivo mouse models of contact hypersensitivity and ex vivo models of human skin were used to delineate the effects and mechanisms of NK1R signaling and the immunosuppressive effects of the contact sensitizer NK1R antagonist MNA in CD. We demonstrated in mice that CD requires NK1R signaling by substance P and hemokinin 1. Specific deletion of the NK1R in keratinocytes and dendritic cells, but not in mast cells, prevented CD. Skin codelivery of hapten or Ag MNA inhibited neuropeptide-mediated skin inflammation in mouse and human skin, promoted deletion of Ag-specific effector T cells, and increased regulatory T cells, which prevented CD onset and relapses locally and systemically in an Ag-specific manner. Immunoregulation by engineering localized skin neuroimmune networks can be used to treat cutaneous diseases that like CD are caused by type 1 immunity.
Sections du résumé
BACKGROUND
Allergic contact dermatitis (CD) is a chronic inflammatory skin disease caused by type 1 biased adaptive immunity for which there is an unmet need for antigen (Ag)-specific immunotherapies. Exposure to skin sensitizers stimulates secretion of the proinflammatory neuropeptides substance P and hemokinin 1, which signal via the neurokinin-1 receptor (NK1R) to promote the innate and adaptive immune responses of CD. Accordingly, mice lacking the NK1R develop impaired CD. Nonetheless, the role and therapeutic opportunities of targeting the NK1R in CD remain to be elucidated.
OBJECTIVE
We sought to develop an Ag-specific immunosuppressive approach to treat CD by skin codelivery of hapten and NK1R antagonists integrated in dissolvable microneedle arrays (MNA).
METHODS
In vivo mouse models of contact hypersensitivity and ex vivo models of human skin were used to delineate the effects and mechanisms of NK1R signaling and the immunosuppressive effects of the contact sensitizer NK1R antagonist MNA in CD.
RESULTS
We demonstrated in mice that CD requires NK1R signaling by substance P and hemokinin 1. Specific deletion of the NK1R in keratinocytes and dendritic cells, but not in mast cells, prevented CD. Skin codelivery of hapten or Ag MNA inhibited neuropeptide-mediated skin inflammation in mouse and human skin, promoted deletion of Ag-specific effector T cells, and increased regulatory T cells, which prevented CD onset and relapses locally and systemically in an Ag-specific manner.
CONCLUSIONS
Immunoregulation by engineering localized skin neuroimmune networks can be used to treat cutaneous diseases that like CD are caused by type 1 immunity.
Identifiants
pubmed: 35085664
pii: S0091-6749(22)00079-3
doi: 10.1016/j.jaci.2021.12.794
pmc: PMC9271537
mid: NIHMS1774119
pii:
doi:
Substances chimiques
Haptens
0
Neurokinin-1 Receptor Antagonists
0
Receptors, Neurokinin-1
0
Substance P
33507-63-0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
114-130Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR073196
Pays : United States
Organisme : NIAMS NIH HHS
ID : P30 AR039750
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA047904
Pays : United States
Organisme : NIAMS NIH HHS
ID : R21 AR063852
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR071277
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI145881
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA175294
Pays : United States
Organisme : NIAMS NIH HHS
ID : K01 AR067250
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL130191
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR068249
Pays : United States
Organisme : NIAMS NIH HHS
ID : P50 AR070590
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI148690
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR074285
Pays : United States
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
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