Alveolar macrophages drive hepatocellular carcinoma lung metastasis by generating leukotriene B4

Takuto Nosaka, Tomohisa Baba, Yamato Tanabe, Soichiro Sasaki, Tatsunori Nishimura, Yoshiaki Imamura, Hideaki Yurino, Shinichi Hashimoto, Makoto Arita, Yasunari Nakamoto, Naofumi Mukaida

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8 Citations (Scopus)

Abstract

Macrophages in lungs can be classified into two subpopulations, alveolar macrophages (AMs) and interstitial macrophages (IMs), which reside in the alveolar and interstitial spaces, respectively. Accumulating evidence indicates the involvement of IMs in lung metastasis, but the roles of AMs in lung metastasis still remain elusive. An i.v. injection of a mouse hepatocellular carcinoma (HCC) cell line, BNL, caused lung metastasis foci with infiltration of AMs and IMs. Comprehensive determination of arachidonic acid metabolite levels revealed increases in leukotrienes and PGs in lungs in this metastasis model. A 5-lipoxygenase (LOX) inhibitor but not a cyclooxygenase inhibitor reduced the numbers of metastatic foci, particularly those of a larger size. A major 5-LOX metabolite, LTB4, augmented in vitro cell proliferation of human HCC cell lines as well as BNL cells. Moreover, in this lung metastasis course, AMs exhibited higher expression levels of the 5-LOX and LTB4 than IMs. Consistently, 5-LOX-expressing AMs increased in the lungs of human HCC patients with lung metastasis, compared with those without lung metastasis. Furthermore, intratracheal clodronate liposome injection selectively depleted AMs but not IMs, together with reduced LTB4 content and metastatic foci numbers in this lung metastasis process. Finally, IMs in mouse metastatic foci produced CCL2, thereby recruiting blood-borne, CCR2-expressing AMs into lungs. Thus, AMs can be recruited under the guidance of IM-derived CCL2 into metastatic lungs and can eventually contribute to the progression of lung metastasis by providing a potent arachidonic acid-derived tumor growth promoting mediator, LTB4.

Original languageEnglish
Pages (from-to)1839-1852
Number of pages14
JournalJournal of Immunology
Volume200
Issue number5
DOIs
Publication statusPublished - 2018 Mar 1

ASJC Scopus subject areas

  • Immunology

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    Nosaka, T., Baba, T., Tanabe, Y., Sasaki, S., Nishimura, T., Imamura, Y., Yurino, H., Hashimoto, S., Arita, M., Nakamoto, Y., & Mukaida, N. (2018). Alveolar macrophages drive hepatocellular carcinoma lung metastasis by generating leukotriene B4 Journal of Immunology, 200(5), 1839-1852. https://doi.org/10.4049/jimmunol.1700544