Peripheral endomorphins drive mechanical alloknesis under the enzymatic control of CD26/DPPIV

Eriko Komiya; Mitsutoshi Tominaga; Ryo Hatano; Yuji Kamikubo; Sumika Toyama; Hakushun Sakairi; Kotaro Honda; Takumi Itoh; Yayoi Kamata; Munehiro Tsurumachi; Ryoma Kishi; Kei Ohnuma; Takashi Sakurai; Chikao Morimoto; Kenji Takamori

doi:10.1016/j.jaci.2021.08.003

Peripheral endomorphins drive mechanical alloknesis under the enzymatic control of CD26/DPPIV

J Allergy Clin Immunol. 2022 Mar;149(3):1085-1096. doi: 10.1016/j.jaci.2021.08.003. Epub 2021 Aug 17.

Authors

Affiliations

¹ Juntendo Itch Research Center, Institute for Environmental and Gender-Specific Medicine, Graduate School of Medicine, Juntendo University, Chiba, Japan.
² Juntendo Itch Research Center, Institute for Environmental and Gender-Specific Medicine, Graduate School of Medicine, Juntendo University, Chiba, Japan; Anti-Aging Skin Research Laboratory, Graduate School of Medicine, Juntendo University, Chiba, Japan.
³ Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
⁴ Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan.
⁵ Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Atopy (Allergy) Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
⁶ Juntendo Itch Research Center, Institute for Environmental and Gender-Specific Medicine, Graduate School of Medicine, Juntendo University, Chiba, Japan; Department of Dermatology, Juntendo University Urayasu Hospital, Chiba, Japan.
⁷ Juntendo Itch Research Center, Institute for Environmental and Gender-Specific Medicine, Graduate School of Medicine, Juntendo University, Chiba, Japan; Anti-Aging Skin Research Laboratory, Graduate School of Medicine, Juntendo University, Chiba, Japan; Department of Dermatology, Juntendo University Urayasu Hospital, Chiba, Japan. Electronic address: ktakamor@juntendo.ac.jp.

PMID: 34411589
DOI: 10.1016/j.jaci.2021.08.003

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.

Keywords: CD26; dipeptidyl peptidase IV enzyme; endomorphin; mechanical alloknesis; mechanical itch; peripheral μ-opioid receptor; skin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dermatitis, Atopic*
Dipeptidyl Peptidase 4* / genetics
Keratinocytes
Mice
Pruritus
Psoriasis*

Substances

Dipeptidyl Peptidase 4
Dpp4 protein, mouse