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 journalArticlepeer-review

5 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
Pages (from-to)1606-1620
Number of pages15
JournalMucosal Immunology
Volume11
Issue number6
DOIs
Publication statusPublished - 2018 Nov 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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