Pituitary adenylate cyclase-activating polypeptide promotes cutaneous dendritic cell functions in contact hypersensitivity - 03/09/21
, Yoshihiro Ishida, MD, PhD a, Lai San Wong, MD a, d, Judith A. Seidel, PhD a, Yumi Nonomura, MD, PhD a, Chisa Nakashima, MD, PhD a, Saeko Nakajima, MD, PhD a, Akihiko Kitoh, MD, PhD a, Takashi Nomura, MD, PhD a, Teruki Dainichi, MD, PhD a, Tetsuya Honda, MD, PhD a, Wataru Amano, DVM, PhD a, b, Noriko Konishi, PhD b, Mikio Hayashi, PhD b, Mutsuyoshi Matsushita, PhD b, Kenji Kabashima, MD, PhD a, e, ⁎ Abstract |
Background |
Sensory nerves regulate cutaneous local inflammation indirectly through induction of pruritus and directly by acting on local immune cells. The underlying mechanisms for how sensory nerves influence cutaneous acquired immune responses remain to be clarified.
Objective |
This study aimed to explore the effect of peripheral nerves on cutaneous immune cells in cutaneous acquired immune responses.
Methods |
We analyzed contact hypersensitivity (CHS) responses as a murine model of delayed-type hypersensitivity in absence or presence of resiniferatoxin-induced sensory nerve denervation. We conducted ear thickness measurements, flow cytometric analyses, and mRNA expression analyses in CHS.
Results |
CHS responses were attenuated in mice that were denervated during the sensitization phase of CHS. By screening neuropeptides, we found that pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA expression was decreased in the dorsal root ganglia after denervation. Administration of PACAP restored attenuated CHS response in resiniferatoxin-treated mice, and pharmacological inhibition of PACAP suppressed CHS. Flow cytometric analysis of skin-draining lymph nodes showed that cutaneous dendritic cell migration and maturation were reduced in both denervated mice and PACAP antagonist-treated mice. The expression of chemokine receptors CCR7 and CXCR4 of dendritic cell s was enhanced by addition of PACAP in vitro.
Conclusion |
These findings indicate that a neuropeptide PACAP promotes the development of CHS responses by inducing cutaneous dendritic cell functions during the sensitization phase.
Le texte complet de cet article est disponible en PDF.Key words : PACAP, denervation, dendritic cells, contact hypersensitivity, resiniferatoxin, neuropeptides, peripheral sensory nerves
Abbreviations used : BMDC, CGRP, CHS, DC, DNFB, DT, DRG, FITC, KikGR, LN, PACAP, RTX, TC1, TCR, TRPA1, TRPV1
Plan
| This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare of Japan (to K.K.) and the Platform Project for Supporting Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Japan Agency for Medical Research and Development (AMED) under grant JP19gm1210006h0001 (to A.O. and K.K.), and a research grand from Japan Tobacco Inc (to K.K.). |
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| Disclosure of potential conflict of interest: Y. Yamamoto, W. Amano, N. Konishi, M. Hayashi, and M. Matsushita are employed by Japan Tobacco. A. Otsuka has received honoraria from Ono Pharmaceutical; and a research grant from Eisai. Y. Nonomura has received honoraria from Novartis. S. Nakajima has received a research grant from Toyota. A. Kitoh has received honoraria from Novartis, Sanofi, Chugai Pharmaceutical, Kyowa Hakko Kirin, and Tanabe Mitsubishi. T. Dainichi has received a research grant from Rohto Pharmaceutical. T. Honda has received honoraria from Eli Lilly Japan, Janssen Pharmaceutical, Taiho Pharmaceutical, and Celgene; and research grants from Eisai, Novartis, Kyowa Hakko Kirin, Maruho, AbbVie, Sanofi, Torii Pharmaceutical, and Tanabe Mitsubishi. K. Kabashima has received research consulting fees or advisory board honoraria from Chugai Pharmaceutical, Japan Tobacco, Maruho, and Pola Pharma; and research grants from AbbVie, Eli Lilly Japan, Japan Tobacco, Kyorin Pharmaceutical, Kyowa Hakko Kirin, LEO Pharma, Ono Pharmaceutical, P&G Japan, Pola Pharma, Sanofi, and Tanabe Mitsubishi. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 148 - N° 3
P. 858-866 - septembre 2021 Retour au numéro
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