Sphingosine 1-phosphate receptor modulator ONO-4641 stimulates CD11b+Gr-1+ cell expansion and inhibits lymphocyte infiltration in the lungs to ameliorate murine pulmonary emphysema

Takanori Asakura, Makoto Ishii, Ho Namkoong, Shoji Suzuki, Shizuko Kagawa, Kazuma Yagi, Takaki Komiya, Takafumi Hashimoto, Satoshi Okamori, Hirofumi Kamata, Sadatomo Tasaka, Akio Kihara, Ahmed E. Hegab, Naoki Hasegawa, Tomoko Betsuyaku

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Sphingolipids play a pivotal role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, little is known about the precise roles of sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, and its receptor modulation in COPD. In this study, we demonstrated that the S1P receptor modulator ONO-4641 induced the expansion of lung CD11b+Gr-1+ cells and lymphocytopenia in naive mice. ONO-4641-expanded CD11b+Gr-1+ cells showed higher arginase-1 activity, decreased T cell proliferation, and lower IFN-γ production in CD3+ T cells, similar to the features of myeloid-derived suppressor cells. ONO-4641 treatment decreased airspace enlargement in elastase-induced and cigarette smoke-induced emphysema models and attenuated emphysema exacerbation induced by post-elastase pneumococcal infection, which was also associated with an increased number of lung CD11b+Gr-1+ cells. Adoptive transfer of ONO-4641-expanded CD11b+Gr-1+ cells protected against elastase-induced emphysema. Lymphocytopenia observed in these models likely contributed to beneficial ONO-4641 effects. Thus, ONO-4641 attenuated murine pulmonary emphysema by expanding lung CD11b+Gr-1+ cell populations and inducing lymphocytopenia. The S1P receptor might be a promising target for strategies aimed at ameliorating pulmonary emphysema progression.

Original languageEnglish
JournalMucosal Immunology
DOIs
Publication statusAccepted/In press - 2018 Jan 1

Fingerprint

Lysosphingolipid Receptors
Pulmonary Emphysema
Lymphocytes
Lung
Lymphopenia
Pancreatic Elastase
Emphysema
Sphingolipids
Chronic Obstructive Pulmonary Disease
T-Lymphocytes
Pneumococcal Infections
Arginase
Adoptive Transfer
Smoke
Tobacco Products
ceralifimod
Cell Proliferation
Population

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Sphingosine 1-phosphate receptor modulator ONO-4641 stimulates CD11b+Gr-1+ cell expansion and inhibits lymphocyte infiltration in the lungs to ameliorate murine pulmonary emphysema. / Asakura, Takanori; Ishii, Makoto; Namkoong, Ho; Suzuki, Shoji; Kagawa, Shizuko; Yagi, Kazuma; Komiya, Takaki; Hashimoto, Takafumi; Okamori, Satoshi; Kamata, Hirofumi; Tasaka, Sadatomo; Kihara, Akio; Hegab, Ahmed E.; Hasegawa, Naoki; Betsuyaku, Tomoko.

In: Mucosal Immunology, 01.01.2018.

Research output: Contribution to journalArticle

Asakura, Takanori ; Ishii, Makoto ; Namkoong, Ho ; Suzuki, Shoji ; Kagawa, Shizuko ; Yagi, Kazuma ; Komiya, Takaki ; Hashimoto, Takafumi ; Okamori, Satoshi ; Kamata, Hirofumi ; Tasaka, Sadatomo ; Kihara, Akio ; Hegab, Ahmed E. ; Hasegawa, Naoki ; Betsuyaku, Tomoko. / Sphingosine 1-phosphate receptor modulator ONO-4641 stimulates CD11b+Gr-1+ cell expansion and inhibits lymphocyte infiltration in the lungs to ameliorate murine pulmonary emphysema. In: Mucosal Immunology. 2018.
@article{7617230df4804ce988e458b4fc4ad227,
title = "Sphingosine 1-phosphate receptor modulator ONO-4641 stimulates CD11b+Gr-1+ cell expansion and inhibits lymphocyte infiltration in the lungs to ameliorate murine pulmonary emphysema",
abstract = "Sphingolipids play a pivotal role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, little is known about the precise roles of sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, and its receptor modulation in COPD. In this study, we demonstrated that the S1P receptor modulator ONO-4641 induced the expansion of lung CD11b+Gr-1+ cells and lymphocytopenia in naive mice. ONO-4641-expanded CD11b+Gr-1+ cells showed higher arginase-1 activity, decreased T cell proliferation, and lower IFN-γ production in CD3+ T cells, similar to the features of myeloid-derived suppressor cells. ONO-4641 treatment decreased airspace enlargement in elastase-induced and cigarette smoke-induced emphysema models and attenuated emphysema exacerbation induced by post-elastase pneumococcal infection, which was also associated with an increased number of lung CD11b+Gr-1+ cells. Adoptive transfer of ONO-4641-expanded CD11b+Gr-1+ cells protected against elastase-induced emphysema. Lymphocytopenia observed in these models likely contributed to beneficial ONO-4641 effects. Thus, ONO-4641 attenuated murine pulmonary emphysema by expanding lung CD11b+Gr-1+ cell populations and inducing lymphocytopenia. The S1P receptor might be a promising target for strategies aimed at ameliorating pulmonary emphysema progression.",
author = "Takanori Asakura and Makoto Ishii and Ho Namkoong and Shoji Suzuki and Shizuko Kagawa and Kazuma Yagi and Takaki Komiya and Takafumi Hashimoto and Satoshi Okamori and Hirofumi Kamata and Sadatomo Tasaka and Akio Kihara and Hegab, {Ahmed E.} and Naoki Hasegawa and Tomoko Betsuyaku",
year = "2018",
month = "1",
day = "1",
doi = "10.1038/s41385-018-0077-5",
language = "English",
journal = "Mucosal Immunology",
issn = "1933-0219",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Sphingosine 1-phosphate receptor modulator ONO-4641 stimulates CD11b+Gr-1+ cell expansion and inhibits lymphocyte infiltration in the lungs to ameliorate murine pulmonary emphysema

AU - Asakura, Takanori

AU - Ishii, Makoto

AU - Namkoong, Ho

AU - Suzuki, Shoji

AU - Kagawa, Shizuko

AU - Yagi, Kazuma

AU - Komiya, Takaki

AU - Hashimoto, Takafumi

AU - Okamori, Satoshi

AU - Kamata, Hirofumi

AU - Tasaka, Sadatomo

AU - Kihara, Akio

AU - Hegab, Ahmed E.

AU - Hasegawa, Naoki

AU - Betsuyaku, Tomoko

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Sphingolipids play a pivotal role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, little is known about the precise roles of sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, and its receptor modulation in COPD. In this study, we demonstrated that the S1P receptor modulator ONO-4641 induced the expansion of lung CD11b+Gr-1+ cells and lymphocytopenia in naive mice. ONO-4641-expanded CD11b+Gr-1+ cells showed higher arginase-1 activity, decreased T cell proliferation, and lower IFN-γ production in CD3+ T cells, similar to the features of myeloid-derived suppressor cells. ONO-4641 treatment decreased airspace enlargement in elastase-induced and cigarette smoke-induced emphysema models and attenuated emphysema exacerbation induced by post-elastase pneumococcal infection, which was also associated with an increased number of lung CD11b+Gr-1+ cells. Adoptive transfer of ONO-4641-expanded CD11b+Gr-1+ cells protected against elastase-induced emphysema. Lymphocytopenia observed in these models likely contributed to beneficial ONO-4641 effects. Thus, ONO-4641 attenuated murine pulmonary emphysema by expanding lung CD11b+Gr-1+ cell populations and inducing lymphocytopenia. The S1P receptor might be a promising target for strategies aimed at ameliorating pulmonary emphysema progression.

AB - Sphingolipids play a pivotal role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, little is known about the precise roles of sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, and its receptor modulation in COPD. In this study, we demonstrated that the S1P receptor modulator ONO-4641 induced the expansion of lung CD11b+Gr-1+ cells and lymphocytopenia in naive mice. ONO-4641-expanded CD11b+Gr-1+ cells showed higher arginase-1 activity, decreased T cell proliferation, and lower IFN-γ production in CD3+ T cells, similar to the features of myeloid-derived suppressor cells. ONO-4641 treatment decreased airspace enlargement in elastase-induced and cigarette smoke-induced emphysema models and attenuated emphysema exacerbation induced by post-elastase pneumococcal infection, which was also associated with an increased number of lung CD11b+Gr-1+ cells. Adoptive transfer of ONO-4641-expanded CD11b+Gr-1+ cells protected against elastase-induced emphysema. Lymphocytopenia observed in these models likely contributed to beneficial ONO-4641 effects. Thus, ONO-4641 attenuated murine pulmonary emphysema by expanding lung CD11b+Gr-1+ cell populations and inducing lymphocytopenia. The S1P receptor might be a promising target for strategies aimed at ameliorating pulmonary emphysema progression.

UR - http://www.scopus.com/inward/record.url?scp=85052287535&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052287535&partnerID=8YFLogxK

U2 - 10.1038/s41385-018-0077-5

DO - 10.1038/s41385-018-0077-5

M3 - Article

JO - Mucosal Immunology

JF - Mucosal Immunology

SN - 1933-0219

ER -