Peripheral endomorphins drive mechanical alloknesis under the enzymatic control of CD26/DPPIV - 03/03/22
Abstract |
Background |
Mechanical alloknesis (or innocuous mechanical stimuli–evoked itch) often occurs in dry skin–based disorders such as atopic dermatitis and psoriasis. However, the molecular and cellular mechanisms underlying mechanical alloknesis remain unclear. We recently reported the involvement of CD26 in the regulation of psoriatic itch. This molecule exhibits dipeptidyl peptidase IV (DPPIV) enzyme activity and exerts its biologic effects by processing various substances, including neuropeptides.
Objective |
The aim of the present study was to investigate the peripheral mechanisms of mechanical alloknesis by using CD26/DPPIV knockout (CD26KO) mice.
Methods |
We applied innocuous mechanical stimuli to CD26KO or wild-type mice. The total number of scratching responses was counted as the alloknesis score. Immunohistochemical and behavioral pharmacologic analyses were then performed to examine the physiologic activities of CD26/DPPIV or endomorphins (EMs), endogenous agonists of μ-opioid receptors.
Results |
Mechanical alloknesis was more frequent in CD26KO mice than in wild-type mice. The alloknesis score in CD26KO mice was significantly reduced by the intradermal administration of recombinant DPPIV or naloxone methiodide, a peripheral μ-opioid receptor antagonist, but not by that of mutant DPPIV without enzyme activity. EMs (EM-1 and EM-2), selective ligands for μ-opioid receptors, are substrates for DPPIV. Immunohistochemically, EMs were located in keratinocytes, fibroblasts, and peripheral sensory nerves. Behavioral analyses revealed that EMs preferentially provoked mechanical alloknesis over chemical itch. DPPIV-digested forms of EMs did not induce mechanical alloknesis.
Conclusion |
The present results suggest that EMs induce mechanical alloknesis at the periphery under the enzymatic control of CD26/DPPIV.
Le texte complet de cet article est disponible en PDF.Key words : CD26, dipeptidyl peptidase IV enzyme, endomorphin, mechanical alloknesis, mechanical itch, peripheral μ-opioid receptor, skin
Abbreviations used : AD, CD26KO, CGRP, DPPIV, EM, GRP, GRPR, IN, MOR, Mrgpr, NF200, NK1R, Nppb, Npra, NPY, sDPPIV, smDPPIV, SP, TrkB, Ucn3, WT, Y1
Plan
| Supported by a grant-in-aid from the Foundation of Strategic Research Projects in Private Universities from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (grant S1311011 [to K.T.]); Japanese Society for the Promotion of Science Grants-in-Aid for Scientific Research Program (grants 17K16353 [to E.K.], 20K08680 [to E.K.], 18H02783 [to K.O.], 18K07396 [to M.T.], 16H05345 [to C.M.], 16K08997 [to K.T.], and 20H03568 (to K.T.]); the Ministry of Health, Labour, and Welfare, Japan (grants 150401-01 [to C.M.] and 180101-01 [to C.M.]; and a grant from the Lydia O’Leary Memorial Pias Dermatological Foundation (2021 [to M.T.]). |
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| Disclosure of potential conflicts of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 149 - N° 3
P. 1085-1096 - mars 2022 Retour au numéro
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