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

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...

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Published in:	Mucosal immunology 2018-11, Vol.11 (6), p.1606-1620
Main Authors:	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
Format:	Article
Language:	eng
Subjects:	Adoptive Transfer Animals Arginase Azetidines - pharmacology Azetidines - therapeutic use CD11b antigen CD11b Antigen - metabolism CD3 antigen Cell Movement - drug effects Cell Proliferation Cells, Cultured Chronic obstructive pulmonary disease Cigarette smoke Disease Models, Animal Elastase Emphysema Female Humans Lung - immunology Lung diseases Lymphocytes T Metabolites Mice Mice, Inbred C57BL Naphthalenes - pharmacology Naphthalenes - therapeutic use Obstructive lung disease Pulmonary Disease, Chronic Obstructive - drug therapy Pulmonary Emphysema - drug therapy Receptors, Cell Surface - metabolism Receptors, Lysosphingolipid - antagonists & inhibitors Sphingolipids Sphingosine 1-phosphate Suppressor cells T-Lymphocytes - drug effects T-Lymphocytes - immunology γ-Interferon
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Summary:	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.
ISSN:	1933-0219 1935-3456